Methods of treating psychosis

ABSTRACT

Isochromans, isothiochromans, 2-benzoxepins and 2-benzothiepins are described. The compounds possess hypotensive and antipsychotic properties; methods and compositions using them are described.

The present application is a divisional application of Ser. No. 847,371,filed Oct. 31, 1977, now U.S. Pat. No. 4,179,510.

BACKGROUND OF THE INVENTION

1. Field of the Invention

This inventon concerns novel isochromans, isothiochromans, 2-benzoxepinsand 2-benzothiepins, methods for preparing them, and their use ashypotensive agents and antipsychotic agents.

The compounds additionally have other effects on the central nervoussystem, such as antidepressant, antianxiety effects, and can also beused for such indications.

2. The Prior Art

1-Substituted isochromans are known for a variety of uses. For example,U.S. Pat. No. 3,467,675, Sept. 16, 1969 (Petersen), teaches isochromanswhich are disclosed to treat pysiological-psychological abnormalities.Specifically, Petersen teaches the use of the compounds for treatment ofendogenic depression. Japanese Pat. No. J5 1125-287, Nov. 1, 1976(Takeda I) (Derwent 94938X) and Netherlands Pat. No. 7605-36, July 5,1977 (Takeda) (Derwent 50610Y) also teach isochromans. The Takedacompounds are disclosed to be useful as anti-depression agents,analgesics, diuretics, anti-inflammatory agents, hypotensives and forthe treatment of bronchial asthma.

SUMMARY OF THE INVENTION

The invention comprises compounds of the formula: ##STR1## wherein R¹ isthe same or different and is selected from the group consisting of alkylof one through three carbons, alkoxy of one through three carbons,trihaloalkyl of one or two carbons, hydroxy, halo, trihaloalkoxy of oneor two carbons and o-methylenedioxy with the proviso that at least oneR₁ is hydroxy, alkoxy or o-methylenedioxy;

a is one through three;

b is zero or one;

R₂ through R₇ are the same or different and are selected from the groupconsisting of hydrogen, alkyl of one through three carbons, inclusive,hydroxy, alkoxy of one through three carbons; phenyl; halo; cycloalkylof three through six carbons when R₂ and R₃, R₄ and R₅, or R₆ and R₇ aretaken together with the carbon to which they are attached; cycloalkyl offour through seven carbons when R₂ and R₄ or R₄ and R₆ are takentogether with the carbons to which they are attached; and cycloalkyl offive or six carbons, with the overall provisos that no more than onering may be attached to any one carbon and that at least two of R₂through R₇ are hydrogen.

R₈ is alkyl of one through three carbons, hydrogen, or phenylunsubstituted or substituted with a maximum of three substituentsselected from the group consisting of alkyl of one through threecarbons, halo, alkoxy of one through three carbons, and trihaloalkyl ofone or two carbons,

W is oxygen or sulfur;

and A is selected from the group consisting of

(i) --(CH₂)nNR₉ R₁₀, wherein n is one to five with the proviso that whenb is zero, and n is one or two, R₂ through R₅ cannot all be hydrogen atthe same time.

(ii) --(CH₂)m-(OCH₂ CH₂)q-NR₂₁ R₂₂, wherein m and q are each one tothree, and R₂₁ and R₂₂ can be same or different and are selected fromthe group consisting of H, alkyl of one through four carbons, andtogether with the N to which they are attached form heterocyclic ringsof four to six ring atoms, morpholine, and NR₉ R₁₀,

(iii) --(CH₂)m-(OCH₂ CH₂)q-OH wherein m and q are each one to three##STR2##

Wherein NR₉ R₁₀ is a heterocyclic amine selected from the groupconsisting of ##STR3## and

--NHCH₂ CH₂ Ar'

wherein R₁₁ is alkyl of one through four carbons, 2-furyl, Ar, or alkoxyof one to three carbon atoms;

Z is selected from the group consisting of pyridyl, pyrimidinyl,triazinyl, pyrazinyl, pyridazinyl, pyrrolyl, imidazolyl, pyrazolyl,furyl, tetrazyl, oxazolyl, quinoxalinyl, and quinazolinyl, wherein eachmember of the group can be unsubstituted or substituted with one or twosubstituents selected from the group consisting of alkyl of one throughthree carbons, inclusive, alkoxy of one through three carbons,inclusive, hydroxy, halo, and haloalkyl of one through three carbons,inclusive;

R₁₂ is alkyl or alkoxy of one through three carbons, hydroxy, halo,trihalomethyl, R₁₃ through R₂₀ may be the same or different and areselected from the group hydrogen and alkyl of from one to two carbonatoms, inclusive;

c is zero through two;

Ar and Ar' are phenyl unsubstituted or substituted with one throughthree substituents selected from the group consisting of alkyl or alkoxyof one through three carbons, inclusive, hydroxy, halo, and trihaloalkylor trihaloalkoxy of one to two carbons, inclusive.

The preferred compounds of the invention are those having the formula##STR4## wherein

b is zero or one,

a is two or three,

n is one to three

R₂ through R₇ are the same or different and are selected from the groupconsisting of hydrogen, alkyl of one through three carbons, andcycloalkyl of four through seven carbons when R₂ and R₄ or R₄ and R₆ aretaken together with the carbons to which they are attached; and

NR₉ R₁₀ is selected from the group consisting of ##STR5## and --NHCH₂CH₂ Ar'

wherein Ar, Ar', R₈, R₁₂, Z and c are the same as defined above.

Specifically preferred are those compounds of formula I' wherein R₂ andR₃ are both alkyl of from one to three carbon atoms, inclusive, b iszero and R₈ is hydrogen.

The invention also comprises the pharmacologically acceptable acidaddition salts of the formula I compounds. These include but are notlimited to: hydrochlorides, hydrobromides, sulfates, phosphates,acetates, salicylates, pamoates and cyclohexanesulfamates.

The compounds or their acid addition salts in their crystalline statecan be isolated as solvates, i.e., with a discreet quantity of solvent,e.g. water, ethanol, associated physically and thus removable withouteffective alteration of the chemical entity per se.

As used herein, the terms

alkyl (1-3 carbon atoms) refers to methyl, ethyl, propyl, isopropyl,

trihaloalkyl of 1-2 carbons is for example trifluoromethyl,trichloromethyl, 2,2,2-trifluoroethyl,

alkoxy of 1-3 carbon atoms is for example methoxy, ethoxy, propoxy andisopropoxy,

halo refers to chloro, bromo, fluoro, cycloalkyl of 3 through 7 carbonsis for example cyclopropyl, cyclopentyl, cyclohexyl, cycloheptyl,

trihaloalkoxy of 1 to 2 carbons such as 2,2,2-trifluoromethoxy,trichloromethoxy, trifluoromethoxy.

R₁ is o-methylenedioxy means that R₁ taken together with an adjacentcarbon atom is the group ##STR6## There can be no more than oneo-methylenedioxy on the free positions on the ring.

The description of this invention is not intended to be limiting forspecific optically active isomers. All possible isomeric forms of thecompounds are included.

The invention also comprises the use of compounds of formula I to reduceblood pressure in mammals, including man. The compounds wherein R₂ andR₃ are both lower alkyl are particularly effective for reducing bloodpressure.

The invention also comprises the use of compound of formula I asantipsychotic agents.

The invention also comprises pharmaceutical dosage unit forms adaptedfor systemic administration to obtain antihypertensive and antipsychoticeffects in mammals, including man, comprising an effective amount of acompound according to formulas I and Ia, or pharmaceutically acceptableacid addition salts thereof, in combination with pharmaceutical carrierswhich adapt such compounds for systemic administration.

The invention also comprises the preparation of compounds of formula I.

The compounds of formula I are also analgesic and antidepressant agents.

The compounds may be administered in conventional forms such as tabletsor capsules, including the sustained oral release type, powders,elixirs, syrups, suppositories, and intramuscular or intravenousinjections.

DETAILED DESCRIPTION OF THE INVENTION

The compounds of formula I wherein A is --(CH₂)nNR₉ R₁₀ can be preparedaccording to the following schematic flow chart ##STR7##

X is halo,

D is ##STR8## wherein R is alkyl of one through two carbons, i.e. ketalor acetal functionality, and all the other terms are as defined above.When n is 1 in a compound of formula I, it is preferred that X instructure II be bromo. When n is 2 to 5, it is preferred that X bechloro.

The compounds of formula I wherein A is selected from group consistingof ##STR9## can also be prepared in accordance with the above flow chartby substituting ##STR10## wherein D, X, R₈ and R₁₃ through R₂₀ are thesame as above, respectively, for the straight chain compounds of formulaIV.

Step 1 can be performed in the absence of solvent but a solvent such asmethylene chloride, nitromethane tetrahydrofuran (THF), ethylether,carbon disulfide, benzene, or toluene is preferred. Preferredtemperature is about 25° but temperatures from 0° to 60° are acceptable.

Step 2 can be performed in the absence of solvent but use of a solventsuch as methyl, ethyl, propyl, or butyl alcohol, ethylene glycol,dimethylformamide (DMF), or dimethylsulfoxide (DMSO) is preferred. Anexcess amount of base such as triethylamine is used in step 2 to absorbthe acid produced.

The acid catalysts for step 1 include mineral acids and Lewis acids suchas HCl, HBr and H₂ SO₄, BF₃.Et₂ O, p-toluenesulfonic acid (pTsOH),trifluoroacetic acid (TFA), acetic acid, and SnCl₄.

The compounds (I) obtained can be recovered and purified by conventionalmethods, for example, extraction, chromatography, crystallization, andcombinations thereof.

The following is a preferred preparation for the 2-benzoxepines offormula I where n=2. ##STR11##

Step 1' is carried out in the presence of an acid scavenger, forexample, pyridine, and is a conventional acylation reaction.

Step 2' is performed in an aromatic solvent such as toluene, innitromethane or in a halocarbon such as methylene chloride. Othercatalysts such as SnCl₄ or FeCl₃ are usable but AlCl₃ is preferred.Temperature can range from 10° to 100°.

Step 3' may be conducted in non-polar solvents such as THF, ether, ortoluene.

The acid catalysts for step 4' are as described above for producing thecompounds of structure II.

The compounds (II) obtained can be recovered and purified byconventional methods, for example, extraction, chromatography andcrystallization.

The thiols of structure III (W=S) can be prepared from the alcohols viatheir bromides in accordance with the following flow chart, or by otherliterature methods for example, see Frank and Smith, J. Amer. Chem.Soc., 68, 2103 (1946). ##STR12## wherein n is 1 to 5 and a, b, R₁through R₈ and D are as above, and X' is chloro or bromo. The compoundswherein A is the branched alkylene chain can be made using theappropriate starting materials IVa, IVb, and IVc.

In step A, the alcohol of formula IIIa can be converted to the bromideof formula VI by various procedures known to those skilled in the art.For example, it may be reacted with phosphorus tribromide or hydrogenbromide as is described in J. March, "Advanced Organic Chemistry",McGraw-Hill, 1968, p. 343.

In step B the bromide of formula Q is reacted with a mercaptide, forexample sodium mercaptide, to give the thiol of formula IIIb.

In step C the thiol of formula IIIb is reacted with the appropriateacetal, ketal, ketone, or aldehyde in the presence of an acid catalystto give the halide of formula IIb.

The halide IIb can be reacted with amines to form the compounds havingthe formula I'b in the manner described above for the preparation ofcompounds of Formula I. ##STR13##

Similarly, by using the thiol IIIb with starting materials IVa, IVb orIVc followed by reaction with the desired amines there are obtained theappropriate 1-substituted 2-benzothiepins.

The compounds of structure III wherein at least one of R₂ through R₇ isother than hydrogen can be obtained by conventional chemical reactions,for example:

For the preparation of compounds of formula I wherein R₂ through R₇ arealkyl, halo, alkoxy cycloalkyl and b=0,1, the following reactions (1-5)can be followed as examples: ##STR14##

Each acid or ester can then be reduced by conventional procedures (e.g.with sodium borohydride-Ethanol) to the alcohol and subsequently treatedwith compounds IV, IVa, IVb or IVc to give the precursor1-(haloalkyl)-1-R₈ isochromans or benzoxepins which can then be reactedas described above with amines to give the corresponding formula Icompounds. When it is desired that W=S, the thiols can be prepared fromthe alcohols as shown in the flow scheme for preparing compounds offormula IIb.

The above reactions for placing substituents on the carbon alpha to theacid function in a chain are known in the art and are only given asrepresentative. They are not to be construed as limiting.

Reaction type (1) has been described in Organic Syntheses (Wiley)collective volumes I-IV, and in J. March, Advanced Organic Chemistry,McGraw-Hill, (1968) p. 360. Reaction type (2) is also in OrganicSyntheses and in J. March, p. 460 (it is known as theHell-Volhard-Zelinskii reaction).

Reaction type (3) has been described in J. Amer. Chem. Soc., 98, 6750(1976).

Reaction type (4) is known in the art for alkylation at acidic hydrogenssites--this type of reaction can be found in Organic Syntheses (Wiley),Volume 50, p. 58 (1970).

Reaction type (5) can be carried out according to Katzenellenbogen, J.Org. Chem. 38, 2733(1973).

Compounds of formula I wherein A contains oxygen can be prepared inaccordance with the following flow diagram: ##STR15## wherein a, b, R₁through R₈ and NR₂₁ R₂₂ are the same as above, m and q are each one tothree and B' is selected from the group consisting of hydroxy, halo andthe group ##STR16## wherein R' is selected from the group consisting ofhydrogen, lower alkyl of from one to three carbon atoms, NO₂, halo andtrifluoromethyl.

The reaction of step 2a is preferably carried out with VII wherein B' ishalo, (preferred is chlorine) p-nitrobenzenesulfonyl, or other leavinggroup. When B' is hydroxy a prior sulfonation reaction is performed, forexample with p-nitrobenzenesulfonyl chloride, to give VII wherein B' isp-nitrobenzenesulfonyl; this compound then can be reacted with the amineas described below:

When B' is the group ##STR17## wherein R' is the same as above, thereaction of step 2a is conducted by using about 1-10 moles of amine toabout 1 mole of the compound of formula VII, preferably two moles ofamine to about one mole of the compound of formula VII. The reaction isconducted at a temperature of about 20° to 70° for a period of one to 40hours.

When B' is halogen, the reaction of step 2a is conducted in the presenceor absence of a solvent at a temperature of between 20° and 70° for aperiod of one to 40 hours. Solvents that can be utilized include, butare not limited to ethylene glycol, dimethyl formamide, (DMF),tetrahydrofuran, dimethyl sulfoxide (DMSO), with DMF being the preferredsolvent.

Compounds of formula VII wherein B' is substituted benzenesulfonyl areprepared as follows: ##STR18## wherein a, b, m, q, W and R₁ through R₈are the same as above, and R' is as above.

The above reaction may be carried out in the presence or absence of asolvent at a temperature between 20° and 50° for a period of about onehour to ten hours. Solvents that may be used include DMF, THF, methylenechloride and toluene.

The preferred solvent is methylene chloride. Suitable acid acceptorsinclude the trialkylamines, e.g. triethylamine, inorganic salts, e.g.barium carbonate, and DBU. The preferred acid acceptor is triethylamine.

Compounds of formula VII where B' is halo are prepared in accordancewith the following schematic flow chart. ##STR19## where a, b, m, q, R₁through R₈ and W are the same as above.

The reaction may be carried out in the absence or presence of a solventand at a temperature of about 20° to 100° for 20 to 120 hours. Organicor inorganic bases such as barium carbonate, triethylamine or ethyldi-i-propylamine can be used as acid scavengers.

The compounds of formula VIIIa wherein q is two or three may also beprepared from compounds of formula VIIIa wherein q is one in accordancewith the following flow diagram ##STR20## where X is halogen, q' is oneor two and a, b, m, W and R₁ through R₈ are the same as above.

This reaction may be carried out in the absence or presence of asolvent. It is also desirable to use an acid acceptor and to run thereaction for about 20 to 120 hours at a temperature of 20° to 100°. Sameacid scavengers as above can be used.

The compounds of formula VII wherein B is hydroxy and q is one areprepared by reacting a compound of formula II' with ethylene glycol. Thereaction is conducted in the presence of an acid acceptor such asdi-isopropylethylamine at a temperature of between 20° and 100° for aperiod of about 20 to 120 hours.

In all of the procedures described herein, the desired product orintermediates can be obtained from the reaction mixture utilizingstandard methods, for example, extraction, chromatography,crystallization and combinations thereof.

The compounds of formula Ic, wherein b is zero, m is 1, and R₁ -R₅, R₈,R₂₂, NR₂₁, a, q, and W are as defined above, are advantageously preparedby the route described in the following chart: ##STR21## wherein R" isalkyl of one through three carbon atoms, inclusive.

Step a is advantageously carried out in the presence of acids such asBF₃ Et₂ O; trifluoroacetic acid, p-toluenesulfonic acid, in solventssuch as nitromethane or methylene chloride, at 0° to about 30° C.

Step b is carried out by use of conventional reducing agents, e.g.lithium aluminum hydride in non-polar solvents such as tetrahydrofuranat 0° to 30° C.

Step c is advantageously performed by reaction of an easily cleavableether (e.g. tetrahydropyranyl ether) of the desired haloalkoxyalkanol onthe alkoxide of compound II' at 20°-100° C. in a compatible non-polarsolvent followed by cleavage of the ether under acidic conditions togive the alcohol VIII'; this can then be subsequently converted to theamine product using conditions described above in the process forconverting compounds of formula VIIIa to their corresponding amines.

Pharmaceutically acceptable acid addition salts of the compounds (I) areprepared by reacting the free base of a compound of formula (I) with astoichiometric amount of an acid, such as hydrogen chloride, hydrogenbromide, hydrogen iodide, sulfuric acid, phosphoric acid, acetic acid,propionic acid, butyric acid, lactic acid, citric acid, succinic acid,benzoic acid, salicylic acid, pamoic acid, phthalic acid,cyclohexanesulfamic acid, and the like.

This invention relates also to pharmaceutical dosage unit forms forsystemic administration (oral and parenteral and rectal administration)for treating hypertensive mammals, including humans. The term "dosageunit form" as used in this specification and in the claims refers tophysically discrete units suitable as unitary dosages for mammaliansubjects, each unit containing a pre-determined quantity of theessential active ingredient, i.e., a compound (I) or a pharmaceuticallyacceptable acid addition salt thereof calculated to produce the desiredeffect, in combination with the required pharmaceutical means whichadapt the said ingredient for systemic administration. Examples ofdosage unit forms in accordance with this invention are tablets,capsules, orally administered liquid preparations in liquid vehicles,sterile preparations in liquid vehicles for intramuscular andintravenous administration, suppositories, and sterile dry preparationsfor the extemporaneous preparation of sterile injectable preparations ina liquid vehicle. Solid diluents or carriers for the solid oralpharmaceutical dosage unit forms are selected from the group consistingof lipids, carbohydrates, proteins and mineral solids, for example,starch, sucrose, kaolin, dicalcium phosphate, gelatin, acacia, cornsyrup, corn starch, talc and the like. Capsules, both hard and soft, areformulated with conventional diluents and excipients, for example,edible oils, talc, calcium carbonate, calcium stearate and the like.Liquid preparations for oral administration are prepared in water oraqueous vehicles which advantageously contain suspending agents, such asfor example, ethanol, sodium carboxymethylcellulose, acacia, polyvinylpyrrolidone, polyvinyl alcohol and the like. In the instance ofinjectable forms, they must be sterile and must be fluid to the extentthat easy syringeability exists. Such preparations must be stable underthe conditions of manufacture and storage, and ordinarly contain inaddition to the basic solvent or suspending liquid, preservatives in thenature of bacteristatic and fungicistatis agents, for example, parabens,chlorobutanol, benzyl, alcohol, phenol, thimerosal, and the like. Inmany cases it is preferable to include isotonic agents, for examplesugars or sodium chloride. Carriers and vehicles include vegetable oils,ethanol and polyols, for example, glycerol, propylene glycol, liquidpolyethylene glycol, and the like. Any solid preparations for subsequentextemporaneous preparation of sterile injectable preparations aresterilized, preferably by exposure to a sterilizing gas, such as forexample ethylene oxide. The aforesaid carriers, vehicles, diluents,excipients, preservatives, isotonic agents and the like constitute thepharmaceutical means which adapt the preparations for systemicadministration.

For animals, food premixes with starch, oatmeal, dried fishmeat,fishmeat, fishmeal, flour, and the like can be prepared.

For CNS disease, a daily dose of 5 to 600 mg is indicated,preferentially 10 to 200 mg; in unit of two or three subdivided doses,and the exact amount is adjusted based on the weight, age, and conditionof the patient.

The pharmaceutical dosage unit forms are prepared in accordance with thepreceding general description to provide from about 0.5 mg to about 100mg of the essential active ingredient per dosage unit form. The amountof the essential active ingredient provided in the pharmaceutical dosageunit forms is based on the finding that the effective amount ofcompounds of the invention and acid addition salts thereof, forobtaining a hypotensive effect in mammals is within a range from about0.1 mg per kg to about 35 mg/kg, preferably 0.3 to 15 mg/kg.

The active ingredients of this invention can also be compounded incombination with other ingredients. The amount of such other activeingredients is to be determined with reference to the usual dosage ofeach such ingredient. Thus these novel compounds can be combined withother hypotensive agents such as α-methyldopa (100-250 mg); withdiuretics such as hydrochlorothiazide (10-50 mg); peripheralvasodilators such as hydralazine (10-100 mg); tranquilizers such asmeprobamate (200-400 mg), diazepam (2-10 mg) muscle relaxants, such ascarisoprodol (200-400 mg).

The tranquilization activity of the new compounds of formulae I andtheir pharmacologically acceptable acid addition salts are tested inmice as follows:

Chimney test: [Med. Exp. 4, 145 (1961)]: The test determines the abilityof mice to back up and out of a vertical glass cylinder within 30seconds. At the effective dosage, 50% of the mice failed doing it.

Dish test: Mice in Petri dishes (10 cm. diameter, and 5 cm. high),partially embedded in wood shavings, climb out in a very short time,when not treated. Mice remaining in the dish for more than 3 minutesindicates tranquilization. ED₅₀ equals the dose of test compound atwhich 50% of the mice remain in the dish.

Pedestal test: The untreated mouse leaves the pedestal in less than aminute to climb back to the floor of the standard mouse box.Tranquilized mice will stay on the pedestal for more than one minute.

Nicotine antagonism test: Mice in a group of 6 are injected with thetest compound. Thirty minutes later the mice including control(untreated) mice are injected with nicotine salicylate (2 mg./kg.). Thecontrol mice show overstimulation, i.e. (1) running convulsions,following by (2) tonic extensor fits; followed by (3) deaths.Pretreatment with an active sedative or tranquilizing compound protectsmice against (2) and (3).

TESTING FOR ANXIETY Prolongation of Hypoxic survival:

Pretreatment of mice exposed to the stress of progressive hypoxia andhyperapnia with anxiolytics results in a prolongation of survival. MaleCF-1 derived mice are used in these studies. Thirty minutes afterintraperitoneal pretreatment (test agent suspended in 0.25%methylcellulose or vehicle alone, 1 cc/100 gm body weight) the mice areplaced singly in 125 ml. Erlenmeyer flasks. The receptacles are tightlystoppered and the survival time (time from stoppering to the lastrespiratory effort) of each animal noted. Each compound is tested atthree or more doses spaced at 0.3 log intervals. Six mice are used perdose with six vehicle injected controls run simultaneously. The mean(15-18 minutes) and standard deviation (1-2 minutes) of the survivaltime for the vehicle treated mice are used to convert the data to aquantal form in the following manner. All survival times that differedfrom the mean of the controls by more than 2 standard deviations arescored as a drug effect. ED₅₀ s are calculated by the method of Spearmanand Karber (Finney, D. J., Statistical Method in Biological Assay,Hafner Publ., Co., N.Y., 1952).

The novel compounds of formula I and pharmacologically acceptable acidaddition salts thereof also have antidepressant activity.

The main function of an anti-depressant is to return the depressedindividual to normal function. This should be carefully differentiatedfrom psychic stimulants such as the amphetamines which producedoverstimulation in the normal individual.

Many different methods have been and are used to evaluate antidepressantactivity. In general these methods involve antagonism to a depressantsuch as reserpine or tetrabenazine or a synergistic increase of thetoxicity of certain compounds (i.e., yohimbine or3,4-dihydroxyphenylalanine) and comparison of the drug action of the newcompound with other known antidepressants. No single test alone candetermine whether or not a new compound is an antidepressant or not, butthe profile evidenced by various tests will establish thatantidepressant action is present. A number of such tests are describedbelow.

Hypothermic tests with oxotremorine[1-[4-(pyrrolidinyl)-2-butynyl]-2-pyrrolidinone]

Oxotremorine (as well as apomorphine and tetrabenzzine) produceshypothermic responses in mice. This response is blocked byanticholinergics and antidepressants such as atropine and imipramine.

Oxotremorine produced a very pronounced hypothermia which reaches a peak60 minutes after administration. When administered at 0.6 mg/kg the bodytemperature of a mouse is decreased about 13° F. (when the mouse is keptat room temperature). This temperature decrease is antagonized byantidepressants, e.g., desipramine, imipramine, and amitriptyline.

The present compounds are tested as follows. Groups of four male miceweighing 18-22 g (Strain CF1, Carworth Farms) are injectedintraperitoneally with the test compound prepared in 0.25%methylcellulose and placed in plastic cages. Thirty minutes later 1mg/kg oxotremorine hydrochloride is injected subcutaneously. The miceare placed in a refrigerator maintained at 19° C. Thirty minutes laterthe intraperitoneal temperature is measured using a thermistor probe. Anincrease of 4° F. in the body temperature of the treated mouse(oxotremorine and test compound) over the control mouse (oxotremorinetreated only) is indicative of antidepressive activity.

The same compounds were also tested for potentiation of yohimbineaggregation toxicity. The LD₅₀ of yohimbine hydrochloride in mice is 45mg/kg, i.p. Administration of 20 mg/kg. of yohimbine hydrochloride isnon-lethal. If an antidepressant is administered prior to the yohimbinehydrochloride (20 mg/kg) the lethality of the yohimbine hydrochloride isincreased.

Eight male CF1 mice, 18-22 g. are injected with yohimbine hydrochloridein saline solution. After four hours the LD₅₀ s are determined. Groupsof eight mice are injected with the antidepressant 30 minutes before theadministration of yohimbine hydrochloride [YCl] (20 mg/kg). No mice oronly one mouse is killed from 20 mg/kg of [YCl]. If [YCl] isadministered in the presence of an antidepressant an increase in thetoxicity of [YCl] is found. The ED₅₀ is the dosage of test compoundwhich causes 50% of the mice to die.

Also the compounds are tested for the potentiation of apomorphinegnawing. A group of 4 mice (male, CF1, 18-22 g) are administered thetest compound intraperitoneally 1 hour prior to the subcutaneousinjection of apomorphine hydrochloride 10 mg/kg. The mice are thenplaced in a plastic box (6×11×5 inches) lined at the bottom with acellophane-backed, absorbent paper. The degree of damage to the paper atthe end of 30 minutes is scored from zero to 4. The scores 2 to 4indicate that the compound is a potentiator of apomorphine in this test.

Results in the above tests show that the compounds of formula I and thepharmacologically acceptable acid addition salts thereof can be used asantidepressants, sedatives, and antianxiety drugs in mammals to achievenormalcy in the depressed or anxious individual.

As antipsychotics-neuroleptics the compounds of formula I and theirpharmacologically acceptable acid addition salts can be used in dosagesof 1-300 mg/day and preferably 5-250 mg/day in oral or injectablepreparations, as described above, to alleviate psychotic states such asschizophrenia, manic depressions, etc. The exact amounts to be given aredependent on the age, weight, and condition of the patient.

The following examples and preparations describe the manner and processof making and using the invention and set forth the best modecontemplated by the inventor of carrying out the invention but are notto be construed as limiting.

All temperatures are in degrees centigrade.

The compounds of this invention show potent hypotensive activity on oraladministration to normotensive rats. A 4 mm Hg decrease in Mean ArterialPressure when measured at 4 hours or 24 hours after administration of 50mg/kg of drug is considered statistically significant. By far themajority of the compounds of this invention give blood pressure drops ofgreater than 8 mm Hg, and some of them have the desirable feature ofbeing of longer duration of action (beyond 24 hours).

Also, in the accepted test methodology for neuroleptic (antipsychotic)activity, such as the inhibition of amphetamine aggregation toxicity(Weaver and Kerley, J. Pharm. and Exp. Therap., 135, 240 (1962)) thedose required to inhibit death of 50% of animals previously challengedwith amphetamine gives a measure of the activity of the drug; the lowerthe dose required, the more potent the drug. Mice are injected with thedrug subcutaneously. Inhibition at a dose of 25 mg/kg is consideredsignificant. The potent compounds of this invention show a desirablelevel of death inhibition at a dose of 15 mg/kg or less.

In other accepted tests for antipsychotic activity, as, for example,reversal of hypothermia caused by oxotremorine again the potentcompounds of this invention showed reversal at a dose of less than 15mg/kg; reversal at a dose of 40 mg/kg is considered significant.

HPLC=high performance liquid chromatography.

SSB refers to Skellysolve B®, an isomeric mixture of hexane.

Preparation 17,8-Dimethoxy-1-bromomethyl-1,3,4,5-tetrahydro-2-benzoxepin

A solution of 5.00 g. of 3-(3,4-dimethoxyphenyl)-1-propanol, 9.76 ml ofbromoacetaldehyde diethyl acetal, 2.0 ml of trifluoroacetic acid, and125 ml of nitromethane is heated at 65° under a nitrogen atmosphere for2 hours. After cooling, the reaction mixture is extracted with methylenechloride and aqueous sodium bicarbonate. The organic layer is taken todryness in vacuo and the residue is chromatographed first with 100% CH₂Cl₂ and a second time with 10% ethyl acetate:SSB to give 300 g of7,8-dimethoxy-1-bromomethyl-1,3,4,5-tetrahydro-2-benzoxepin, m.p.44°-45°.

Following the procedure of Preparation 1, but substituting theappropriate 3-(substituted-phenyl)-1-propanol, for3-(3,4-dimethoxyphenyl)-1-propanol the 1-bromomethyl-2-benzoxepins ofTable 1 can be prepared.

TABLE 1

1. 9-methoxy-8-propyl-1-bromomethyl-1,3,4,5-tetrahydro-2-benzoxepin,

2. 9-methoxy-1-bromomethyl-1,3,4,5-tetrahydro-2-benzoxepin,

3. 6,7-dimethoxy-1-bromomethyl-1,3,4,5-tetrahydro-2-benzoxepin,

4. 7-ethoxy-1-bromomethyl-1,3,4,5-tetrahydro-2-benzoxepin,

5. 7,8,9-trimethoxy-1-bromomethyl-1,3,4,5-tetrahydro-2-benzoxepin,

6. 7-hydroxy-6-methoxy-1-bromomethyl-1,3,4,5-tetrahydro-2-benzoxepin,

7. 8-bromo-7-methoxy-1-bromomethyl-1,3,4,5-tetrahydro-2-benzoxepin,

8. 7-methoxy-8,9-dichloro-1-bromomethyl-1,3,4,5-tetrahydro-2-benzoxepin,

9.7-methoxy-8-trifluoromethyl-1-bromomethyl-1,3,4,5-tetrahydro-2-benzoxepin,

10. 7,8-methylenedioxy-1-bromomethyl-1,3,4,5-tetrahydro-2-benzoxepin,

11. 7-methoxy-5-methyl-1-bromomethyl-1,3,4,5-tetrahydro-2-benzoxepin,

12.7,9-dimethoxy-4,5-dimethyl-1-bromomethyl-1,3,4,5-tetrahydro-2-benzoxepin,

13.7,8,9-trimethoxy-4-methyl-1-bromomethyl-1,3,4,5-tetrahydro-2-benzoxepin,

14. 9-methoxy-4-phenyl-1-bromomethyl-1,3,4,5-tetrahydro-2-benzoxepin,

15. 7-hydroxy-5-bromo-1-bromomethyl-1,3,4,5-tetrahydro-2-benzoxepin,

16.7,8-dimethoxy-5,5-dimethyl-1-bromomethyl-1,3,4,5-tetrahydro-2-benzoxepin,

17.7,8-dimethoxy-4,4-dimethyl-1-bromomethyl-1,3,4,5-tetrahydro-2-benzoxepin,

18.-bromomethyl-8,9-dimethoxy-1,3,4,5-tetrahydro[spiro-4(3H),1'-cyclobutane],

19.6-bromomethyl-8,9-dipropyloxy-2,3,3a,4,6,10b-hexahydro-1H-benz[c]cyclopent[e]oxepin,

20.4-cyclopentyl-8,9-dimethoxy-1-bromomethyl-1,3,4,5-tetrahydro-2-benzoxepin,

21.7,8-dihydroxy-5-propyl-1-bromomethyl-1,3,4,5-tetrahydro-2-benzoxepin,

22.7,8-dimethoxy-9-trifluoromethyl-1-bromomethyl-1,3,4,5-tetrahydro-2-benzoxepin.

Preparation 1A7,8-Dimethoxy-1-chloroethyl-1,3,4,5-tetrahydro-2-benzoxepin

To 19.86 g. (0.149 moles) of AlCl₃ in 200 ml of CH₂ Cl₂ was added 14.20ml (0.149 moles) of 3-chloropropionylchloride. The mixture is stirredfor 15 minutes under a N₂ atmosphere and then 38.00 g (0.0992 moles) ofthe 3-chloropropionate of 3-(3,4-dimethoxyphenyl)propanol in 200 ml ofCH₂ Cl₂ is added over a period of 15 min. from a dropping funnel. Afterstirring at room temperature for 30 min., the reaction mixture is heatedat reflux for an additional 3.6 hours. The reaction mixture is thencooled and aqueous sodium bicarbonate is added until gas evolutionceases. The organic layer is filtered through sodium sulfate and takento dryness. The residue is chromatographed using 20% EtOAc:Skellysolve Bas eluant.

A tetrahydrofuran solution of3-chloro-4',5'-dimethoxy-3'-[3-(3-chloropropionoxy)propyl]propiophenone(about 40 g.) is added dropwise to an ice-cooled mixture of 7.3 g. oflithium aluminum hydride in tetrahydrofuran. After stirring for 20minutes the reaction mixture is treated with 7.3 ml water, 7.3 ml 15%sodium hydroxide, and 21 ml water. The resulting suspension is filteredthrough Celite and the salts washed with ether. The filtrate isextracted with brine and the organic phase is filtered through sodiumsulfate and concentrated.

The crude product is dissolved in 500 ml of methylene chloride andtreated with 13 g of p-toluenesulfonic acid monohydrate. After stirringfor 10 minutes the blue-green solution is extracted with aqueous sodiumbicarbonate and brine. The organic layer is filtered through sodiumsulfate and taken to dryness. Chromatography on silica gel with 20%ethyl acetate in Skellysolve B gives 14.7 g of7,8-dimethoxy-1-chloroethyl-1,3,4,5-tetrahydro-2-benzoxepin.

Following the procedure of preparation 1A, but substituting theappropriate 3-substituted-phenylpropanol for3-(3,4-dimethoxyphenyl)propanol, the 1-chloroethylbenzoxepins of Table1A were prepared.

TABLE 1A

1. 9-methoxy-8-propyl-1-chloroethyl-1,3,4,5-tetrahydro-2-benzoxepin,

2. 9-methoxy-1-chloroethyl-1,3,4,5-tetrahydro-2-benzoxepin,

3. 6,7-dimethoxy-1-chloroethyl-1,3,4,5-tetrahydro-2-benzoxepin,

4. 7-ethoxy-1-chloroethyl-1,3,4,5-tetrahydro-2-benzoxepin,

5. 7,8,9-trimethoxy-1-chloroethyl-1,3,4,5-tetrahydro-2-benzoxepin,

6. 7-hydroxy-6-methoxy-1-chloroethyl-1,3,4,5-tetrahydro-2-benzoxepin,

7. 8-bromo-7-methoxy-1-chloroethyl-1,3,4,5-tetrahydro-2-benzoxepin,

8. 7-methoxy-8,9-dichloro-1-chloroethyl-1,3,4,5-tetrahydro-2-benzoxepin,

9.7-methoxy-8-trifluoromethyl-1-chloroethyl-1,3,4,5-tetrahydro-2-benzoxepin,

10. 7,8-methylenedioxy-1-chloroethyl-1,3,4,5-tetrahydro-2-benzoxepin,

11. 7-methoxy-5-methyl-1-chloroethyl-1,3,4,5-tetrahydro-2-benzoxepin,

12.7,9-dimethoxy-4,5-dimethyl-1-chloroethyl-1,3,4,5-tetrahydro-2-benzoxepin,

13.7,8,9-trimethoxy-4-methyl-1-chloroethyl-1,3,4,5-tetrahydro-2-benzoxepin,

14. 9-methoxy-4-phenyl-1-chloroethyl-1,3,4,5-tetrahydro-2-benzoxepin,

15. 7-hydroxy-5-bromo-1-chloroethyl-1,3,4,5-tetrahydro-2-benzoxepin,

16.7,8-dimethoxy-5,5-dimethyl-1-chloroethyl-1,3,4,5-tetrahydro-2-benzoxepin,

17.7,8-dimethoxy-4,4-dimethyl-1-chloroethyl-1,3,4,5-tetrahydro-2-benzoxepin,

18.1-(2-chloroethyl)-1,5-dihydro-7,8-dimethoxy-spiro[2-benzoxepin-4(3H),1'-cyclopentane],

19.6-chloroethyl-8,9-dipropyloxy-2,3,3a,4,6,10b-hexahydro-1H-benzo[c]cyclopent[e]oxepin,

20.4-cyclopentyl-8,9-dimethoxy-1-chloroethyl-1,3,4,5-tetrahydro-2-benzoxepin,

21.7,8-dihydroxy-5-propyl-1-chloroethyl-1,3,4,5-tetrahydro-2-benzoxepin,

22.7,8-methoxy-9-trifluoromethyl-1-chloroethyl-1,3,4,5-tetrahydro-2-benzoxepin.

Preparation 1' Preparation of 3-(3,4-dimethoxyphenyl)-1-propanethiol

A mixture of 5.00 g (25.5 mmoles) of 3-(3,4-dimethoxyphenyl)propanol,1.94 g (25.5 mmoles) of thiourea, and 8.5 ml of 48% hydrobromic acid isheated on steam bath for 1 hour, allowed to stand overnight at roomtemperature, and then heated again on a steam bath for 2 hours. Aftercooling, the reaction mixture is treated with 76.5 ml of 1 M sodiumhydroxide and heated on the steam bath for 11/2 hours. After cooling,the reaction mixture is made acidic with 1 N hydrochloric acid andextracted with methylene chloride (followed by a brine wash). Silica gelchromatography using 10% ethyl acetate/Skellysolve B as eluent gives0.67 g of 3-(3,4-dimethoxyphenyl)-1-propanethiol.

Following the procedure of Preparation 1', but substituting theappropriate 3-substituted-phenyl-1-propanol for3-(3,4-dimethoxyphenyl)-1-propanol, the phenyl-1-propanethiols of Table1' can be prepared.

TABLE 1'

1. 3-(4,5-methoxypropylphenyl)-1-propanethiol,

2. 3-(5-methoxyphenyl)-1-propanethiol,

3. 3-(2,3-dimethoxyphenyl)-1-propanethiol,

4. 3-(3-ethoxyphenyl)-1-propanethiol,

5. 3-(3,4,5-trimethoxyphenyl)-1-propanethiol,

6. 3-(3-hydroxy-2-methoxyphenyl)-1-propanethiol,

7. 3-(4-bromo-3-methoxyphenyl)-1-propanethiol,

8. 3-(4,5-dichloro-3-methoxyphenyl)-1-propanethiol,

9. 3-(3-methoxy-4-trifluoromethylphenyl)-1-propanethiol,

10. 3-(3,4-methylenedioxyphenyl)-1-propanethiol,

11. 3-(3-methoxyphenyl)-3-methyl-1-propanethiol,

12. 3-(3,5-dimethoxyphenyl)-2,3-dimethyl-1-propanethiol,

13. 3-(3,4,5-trimethoxyphenyl)-2-methyl-1-propanethiol,

14. 3-(5-methoxyphenyl)-2-phenyl)-1-propanethiol,

15. 3-(3-hydroxyphenyl)-3-bromo-1-propanethiol,

16. 3-(3,4-dimethoxyphenyl)-3,3-dimethyl-1-propanethiol,

17. 3-(3,4-dimethoxyphenyl)-2,2-dimethyl-1-propanethiol,

18. 1-[(3,4-dimethoxyphenyl)methyl]cyclopent-1-yl-methanethiol,

19. 2-(3,4-dipropyloxyphenyl)cyclopent-1-yl-methanethiol,

20. 3-[(3,4-dimethoxyphenyl)-2-cyclopentyl)]-1-propanethiol,

21. 3-(3,4-dihydroxyphenyl)-3-n-propyl-1-propanethiol,

22. 3-(3,4-dimethoxy-5-trifluoromethylphenyl)-1-propanethiol.

Preparation 1B7,8-Dimethoxy-1-bromomethyl-1,3,4,5-tetrahydro-2-benzothiepin

A mixture of 0.67 g of 3-(3,4-dimethoxyphenyl)-1-propanethiol, 1.0 g ofbromoacetaldehyde diethylacetal, 0.16 ml of trifluoroacetic acid, and 25ml. of nitromethane as solvent is stirred at room temperature for 1hour, stored overnight in the freezer, and then heated at 70° for 2hours after an additional 0.05 ml trifluoroacetic acid is added. Aftercooling, the reaction mixture is extracted with methylene chloride andaqueous sodium bicarbonate. The organic layer is taken to dryness, andthe residue is chromatographed one time on silica gel with methylenechloride as eluent and a second time with 10% ethyl acetate/SkellysolveB as eluent to yield7,8-dimethoxy-1-bromomethyl-1,3,4,5-tetrahydro-2-benzothiepin.

Following the procedure of preparation 1B, but substituting theappropriate 3-phenyl-1-propanethiol from Table 1' for3-(3,4-dimethoxyphenyl)-1-propanethiol, the1-bromomethyl-2-benzothiepins of Table 1B can be prepared.

TABLE 1B

1. 7-propyl-9-methoxy-1-bromomethyl-1,3,4,5-tetrahydro-2-benzothiepin,

2. 9-methoxy-1-bromomethyl-1,3,4,5-tetrahydro-2-benzothiepin,

3. 6,7-dimethoxy-1-bromomethyl-1,3,4,5-tetrahydro-2-benzothiepin,

4. 7-ethoxy-1-bromomethyl-1,3,4,5-tetrahydro-2-benzothiepin,

5. 7,8,9-trimethoxy-1-bromomethyl-1,3,4,5-tetrahydro-2-benzothiepin,

6. 7-hydroxy-6-methoxy-1-bromomethyl-1,3,4,5-tetrahydro-2-benzothiepin,

7. 8-bromo-7-methoxy-1-bromomethyl-1,3,4,5-tetrahydro-2-benzothiepin,

8.8,9-dichloro-7-methoxy-1-bromomethyl-1,3,4,5-tetrahydro-2-benzothiepin,

9.7-methoxy-8-trifluoromethyl-1-bromomethyl-1,3,4,5-tetrahydro-2-benzothiepin,

10. 7,8-methylenedioxy-1-bromomethyl-1,3,4,5-tetrahydro-2-benzothiepin,

11. 7-methoxy-5-methyl-1-bromomethyl-1,3,4,5-tetrahydro-2-benzothiepin,

12.7,9-dimethoxy-4,5-dimethyl-1-bromomethyl-1,3,4,5-tetrahydro-2-benzothiepin

13.7,8,9-trimethoxy-4-methyl-1-bromomethyl-1,3,4,5-tetrahydro-2-benzothiepin,

14. 9-methoxy-4-phenyl-1-bromomethyl-1,3,4,5-tetrahydro-2-benzothiepin,

15. 7-hydroxy-5-bromo-1-bromomethyl-1,3,4,5-tetrahydro-2-benzothiepin,

16.7,8-dimethoxy-5,5-dimethyl-1-bromomethyl-1,3,4,5-tetrahydro-2-benzothiepin

17.7,8-dimethoxy-4,4-dimethyl-1-bromomethyl-1,3,4,5-tetrahydro-2-benzothiepin

18.1-(bromomethyl)-1,5-dihydro-7,8-dimethoxyspiro[2-benzothiepin-4(3H),1'-cyclopentane]

19.6-bromomethyl-8,9-dipropyloxy-2,3,3a,4,6,10b-hexahydro-1H-benzo[c]cyclopent[e]thiepin,

20.4-cyclopentyl-8,9-dimethoxy-1-bromomethyl-1,3,4,5-tetrahydro-2-benzothiepin,

21.7,8-dihydroxy-5-n-propyl-1-bromomethyl-1,3,4,5-tetrahydro-2-benzothiepin,

22.7,8-dimethoxy-9-trifluoromethyl-1-bromomethyl-1,3,4,5-tetrahydro-2-benzoxepin.

Preparation 2 6,7-Dimethoxy-1-(2-chloroethyl)isochroman

To a solution of 3,4-dimethoxyphenethyl alcohol (110 g, 1.233 mole) andchloropropionaldehyde diethyl acetal (40 ml) in 240 ml of nitromethane,8 ml of BF₃ etherate is added. The mixture is stirred for 2 hours atroom temperature under N₂. This, after work up from water and extractingwith methylene chloride gives a yellow oil. This, after columnchromatography (silica gel), gives 45 g (oil) of6,7-dimethoxy-1-(2-chloroethyl)isochroman which is crystallized fromether/pet. ether to give 41 g (70%) of6,7-dimethoxy-1-(2-chloroethyl)isochroman as a white crystallinematerial, m.p. 56°-57.5°.

Analysis Calcd for: C₁₃ H₁₇ ClNO₃ C, 60.82; H, 6.68; Cl, 13.96. Found:C, 60.81; H, 6.65; Cl, 13.96.

Following the procedure of Preparation 2, but substituting theappropriate alcohol for 3,4-dimethoxyphenethyl alcohol, the1-(2-chloroethyl)isochromans of Table 2 can be prepared.

TABLE 2

1. 8-methoxy-7-propyl-1-(2-chloroethyl)isochroman,

2. 8-methoxy-1-(2-chloroethyl)isochroman,

3. 5,6-dimethoxy-1-(2-chloroethyl)isochroman,

4. 6-ethoxy-1-(2-chloroethyl)isochroman,

5. 6,7,8-trimethoxy-1-(2-chloroethyl)isochroman,

6. 6-hydroxy-1-(2-chloroethyl)isochroman,

7. 6-methoxy-7-bromo-1-(2-chloroethyl)isochroman,

8. 6-methoxy-7,8-dichloro-1-(2-chloroethyl)isochroman,

9. 6-methoxy-7-trifluoromethyl-1-(2-chloroethyl)isochroman,

10. 6,7-methylenedioxy-1-(2-chloroethyl)isochroman,

11. 6-methoxy-4-methyl-1-(2-chloroethyl)isochroman,

12. 6,8-dimethoxy-3,4-dimethyl-1-(2-chloroethyl)-isochroman,

13. 6,7,8-trimethoxy-3-methyl-1-(2-chloroethyl)isochroman,

14. 8-methoxy-3-phenyl-1-(2-chloroethyl)isochroman,

15. 6-hydroxy-4-bromo-1-(2-chloroethyl)isochroman,

16. 6,7-dimethoxy-4,4-dimethyl-1-(2-chloroethyl)isochroman,

17. 6,7-dimethoxy-3,3-dimethyl-1-(2-chloroethyl)isochroman,

18.1-(2-chloroethyl)-6,7-dimethoxyspiro[1H-2-benzopyran-4(3H),1'-cyclopentane]

19. 5-(2-chloroethyl)-7,8-dipropyloxy-2,3,3a,5,9b,pentahydro-1H-benzo[c]cyclopent[e]pyran

20. 3-cyclopentyl-7,8-dimethoxy-1-(2-chloroethyl)isochroman,

21. 6,7-dihydroxy-4-n-propyl-1-(2-chloroethyl)isochroman,

22. 6,7-dimethoxy-8-trifluoromethyl-1-(2-chloroethyl)isochroman.

Preparation 2A6,7-Dimethoxy-3,4-dihydro-1-(2-chloroethyl)-1H-2-benzothiapyran

To a solution of 3,4-dimethoxy-phenethanethiol and chloropropionaldehydediethyl acetal in nitromethane, BF₃ etherate is added. The mixture isstirred at room temperature under N₂. This, after work up from water,extracting with methylene chloride, on chromatography gives6,7-dimethoxy-1-(2-chloroethyl)-1H-2-benzothiopyran.

Following the procedure of Preparation 2A, but substituting theappropriate thiol of Table 2' for 3,4-dimethoxyphenethanethiol, the1-(2-chloroethyl)-1H-2-benzothiopyrans of Table 2A can be prepared.

TABLE 2'

1. 2-(5-methoxy-4-propylphenyl)-1-ethanethiol,

2. 2-(5-methoxyphenyl)-1-ethanethiol,

3. 2-(2,3-dimethoxyphenyl)-1-ethanethiol,

4. 2-(3-ethoxyphenyl)-1-ethanethiol,

5. 2-(3,4,5-trimethoxyphenyl)-1-ethanethiol,

6. 2-(3-hydroxy-2-methoxyphenyl)-1-ethanethiol,

7. 2-(3-methoxy-4-bromophenyl)-1-ethanethiol,

8. 2-(3-methoxy-4,5-dichlorophenyl)-1-ethanethiol,

9. 2-(3-methoxy-4-trifluoromethylphenyl)-1-ethanethiol,

10. 2-(3,4-methylenedioxyphenyl)-2-ethanethiol,

11. 2-(3-methoxyphenyl)-2-methyl-1-ethanethiol,

12. 2-(3,5-dimethoxyphenyl)-1,2-dimethyl-1-ethanethiol,

13. 2-(3,4,5-trimethoxyphenyl)-2-methyl-1-ethanethiol.

14. 2-(5-methoxyphenyl)-2-phenyl-1-ethanethiol,

15. 2-(3-hydroxyphenyl)-2-bromo-1-ethanethiol,

16. 2-(3,4-dimethoxyphenyl)-2,2-dimethyl-1-ethanethiol,

17. 2-(3,4-dimethoxyphenyl)-1,1-dimethyl-1-ethanethiol,

18. [1-(3,4-dimethoxyphenyl;cyclopent-1-yl]methanethiol,

19. 2-(3,4-dipropyloxyphenyl)cyclopentan-1-thiol,

20. 2-(3,4-dimethoxyphenyl)-2-cyclopentyl-1-ethanethiol,

21. 2-(3,4-dimethoxyphenyl)-2-n-propyl-1-ethanethiol,

22. 2-(3,4-dimethoxy-5-trifluoromethylphenyl)-1-ethanethiol.

TABLE 2A

1. 8-methoxy-7-propyl-1-(2-chloroethyl)-1H-2-benzothiopyran,

2. 8-methoxy-1-(2-chloroethyl)-1H-2-benzothiopyran,

3. 5,6-dimethoxy-1-(2-chloroethyl)-1H-2-benzothiopyran,

4. 6-ethoxy-1-(2-chloroethyl)-1H-2-benzothiopyran,

5. 6,7,8-trimethoxy-1-(2-chloroethyl)-1H-2-benzothiopyran,

6. 6-hydroxy-1-(2-chloroethyl)-1H-2-benzothiopyran,

7. 6-methoxy-7-bromo-1-(2-chloroethyl)-1H-2-benzothiopyran,

8. 6-methoxy-7,8-dichloro-1-(2-chloroethyl)-1H-2-benzothiopyran,

9. 6-methoxy-7-trifluoromethyl-1-(2-chloroethyl)-1H-2-benzothiopyran,

10. 6,7-methylenedioxy-1-(2-chloroethyl)-1H-2-benzothiopyran,

11. 6-methoxy-4-methyl-1-(2-chloroethyl)-1H-2-benzothiopyran, 12.6,8-dimethoxy-3,4-dimethyl-1-(2-chloroethyl)-1H-2-benzothipyran,

13. 6,7,8-trimethoxy-1-(2-chloroethyl)-1H-2-benzothiopyran,

14. 8-methoxy-3-phenyl-1-(2-chloroethyl)-1H-2-benzothiopyran,

15. 6-hydroxy-4-bromo-1-(2-chloroethyl)-1H-2-benzothiopyran,

16. 6,7-dimethoxy-4,4-dimethyl-1-(2-chloroethyl)-1H-2-benzothiopyran,

17. 6,7-dimethoxy-3,3-dimethyl-1-(2-chloroethyl)-1H-2-benzothiopyran,

18.1-(2-chloroethyl)-6,7-dimethoxyspiro[1H-2-benzothiopyran-4-(3H),1'-cyclopentane],

19.5-(2-chloroethyl)-7,8-dipropoxy-2,3,3a,5,9b-pentahydro-1H-benzo[c]cyclopent[e]thiopyran,

20. 3-cyclopentyl-7,8-dimethoxy-1-(2-chloroethyl)-1H-2-benzothiopyran,

21. 6,7-dihydroxy-4-n-propyl-1-(2-chloroethyl)-1H-2-benzothiopyran,

22.6,7-dimethoxy-8-trifluoromethyl-1-(2-chloroethyl)-1H-2-benzothiopyran.

Preparation 2B 2,2-Dimethyl-2-(3,4-dimethoxyphenyl)ethanol

Lithium diisopropylamine (0.0057 m) is generated at -70° from nBull anddiisopropylamine in THF and is added to a solution of 1.00 g. (0.0048 m)of ethyl 3,4-dimethoxyphenylacetate in 20 ml of dry THF. The reaction isstirred under nitrogen at -70° for 30 min. Methyl iodide (0.67 g, 0.0048m) is injected. After 1 hour, another 0.0057 moles of lithiumdiisopropylamine is added, the reaction is stirred for 30 min., andmethyliodide (0.67 g, 0.0048 m) is added. The reaction is warmed to roomtemperature over three hours. The mixture is partitioned betweenmethylene chloride and aqueous sodium bicarbonate. The organic phase isdried (Na₂ SO₄) and concentrated to yield 1.2 g of tan crystalline ethyl2,2-dimethyl-(3,4-dimethoxyphenyl)acetate. This material is dissolved in50 ml of 4:1 ether/THF. Lithium aluminum hydride (0.20 g) is added andthe mixture is stirred and refluxed for 1.5 hrs. Water (0.2 ml), 15%aqueous sodium hydroxide (0.2 m), and water (0.6 ml) are sequentiallyadded. The mixture is filtered through sodium sulfate and thenpartitioned between aqueous sodium carbonate and methylene chloride. Theorganic phase is dried (sodium sulfate) and concentrated to yield 1.01 gof white crystalline 2,2-dimethyl-2-(3,4-dimethoxyphenyl)ethanol.

Preparation 2B' 6,7-Dimethoxy-1-bromomethylisochroman

A mixture of 29.1 g. of 3,4-dimethoxyphenylethanol, 35 ml ofbromoacetaldehyde dimethyl acetal and 5 ml of 48% HBr is stirred at 80°for 1.5 hr. The organic phase is mixed with 200 ml of methylene chlorideand washed with water and then with 200 ml of 10% aqueous potassiumcarbonate. The organics are dried over sodium sulfate andchromatographed over silica gel. The product is crystallized from etherto yield 36.3 g. of the white solid, 70°-80°.

Preparation 2B" 4,4-Dimethyl-6,7-dimethoxy-1-bromomethylisochroman.

A 2,2-Dimethyl-2-(3,4-dimethoxyphenyl)ethanol (0.95 g, 0.0045 m) isstirred with 1.07 g (0.0054 m) of the ethyl acetal of bromoacetaldehydeand 0.19 g (0.0014 m) of BF₃.etherate in 25 ml of nitromethane for 15hours. The mixture is partitioned between methylene chloride and aqueoussodium carbonate. The organic phase is dried over sodium sulfate andconcentrated to yield 1.52 g of4,4-dimethyl-6,7-dimethoxy-1-bromomethylisochroman. The nmr isconsistent with the assigned structure.

Following the procedures of Preparations 2B and 2B', but substitutingthe appropriate alcohols for 3,4-dimethoxyphenethyl alcohol, the1-bromomethylisochromans of Table 2B' can be prepared.

TABLE 2B'

1. 8-methoxy-7-n-propyl-1-bromomethylisochroman,

2. 8-methoxy-1-bromomethylisochroman,

3. 5,6-dimethoxy-1-bromomethylisochroman,

4. 6-ethoxy-1-bromomethylisochroman,

5. 6,7,8-trimethoxy-1-bromomethylisochroman,

6. 6-hydroxy-1-bromomethylisochroman,

7. 6-methoxy-7-bromo-1-bromomethylisochroman,

8. 6-methoxy-7,8-dichloro-1-bromomethylisochroman,

9. 6-methoxy-7-trifluoromethyl-1-bromomethylisochroman,

10. 6,7-methylenedioxy-1-bromomethylisochroman,

11. 6-methoxy-4-methyl-1-bromomethylisochroman,

12. 6,8-dimethoxy-3,4-dimethyl-1-bromomethylisochroman,

13. 6,7,8-trimethoxy-1-bromomethylisochroman,

14. 8-methoxy-3-phenyl-1-bromomethylisochroman,

15. 6-hydroxy-4-bromo-1-bromomethylisochroman,

16. 6,7-dimethoxy-4,4-dimethyl-1-bromomethylisochroman,

17. 6,7-dimethoxy-3,3-dimethyl-1-bromomethylisochroman,

18.1-bromomethyl-6,7-dimethoxyspiro[1H-2-benzopyran-4(3H),1'-cyclopentane],

19.5-bromomethyl-7,8-dipropoxy-2,3,3a,5,9b-pentahydro-1H-benzo[c]cyclopent[e]pyran,

20. 3-cyclopentyl-7,8-dimethoxy-1-bromomethylisochroman,

21. 6,7-dihydroxy-4-n-propyl-1-bromomethylisochroman,

22. 6,7-dimethoxy-8-trifluoromethyl-1-bromomethylisochroman,

Preparation 2C6,7-Dimethoxy-1-bromomethyl-3,4-dihydro-1H-2-benzothiopyran.

A mixture of 3,4-dimethoxyphenylethane thiol, bromoacetaldehydedimethylacetal, and BF₃.etherate in nitromethane is stirred at 40°. Theproduct is dissolved in methylene chloride and washed with aqueoussodium bicarbonate. Chromatography on silica gel is used to isolate theproduct.

Following the procedure of Preparation 2C, but substituting theappropriate thiols for 3,4-dimethoxyphenylethane thiol, the1-bromomethyl-3,4-dihydro-1H-2-benzothiopyrans of Table 2C can beprepared.

TABLE 2C

1. 8-methoxy-7-n-propyl-1-bromomethyl-3,4-dihydro-1H-2-benzothiopyran,

2. 8-methoxy-1-bromomethyl-3,4-dihydro-1H-2-benzothiopyran,

3. 5,6-dimethoxy-1-bromomethyl-3,4-dihydro-1H-2-benzothiopyran,

4. 6-ethoxy-1-bromomethyl-3,4-dihydro-1H-2-benzothiopyran,

5. 6,7,8-trimethoxy-1-bromomethyl-3,4-dihydro-1H-2-benzothiopyran,

6. 6-hydroxy-1-bromomethyl-3,4-dihydro-1H-2-benzothiopyran,

7. 6-methoxy-7-bromo-1-bromomethyl-3,4-dihydro-1H-2-benzothiopyran,

8. 6-methoxy-7,8-dichloro-1-bromomethyl-3,4-dihydro-1H-2-benzothiopyran,

9.6-methoxy-7-trifluoromethyl-1-bromomethyl-3,4-dihydro-1H-2-benzothiopyran,

10. 6,7-methylenedioxy-1-bromo-3,4-dihydro-1H-2-benzothiopyran,

11. 6-methoxy-4-methyl-1-bromomethyl-3,4-dihydro-1H-2-benzothiopyran,

12.6,8-dimethoxy-3,4-dimethyl-1-bromomethyl-3,4-dihydro-1H-2-benzothiopyran,

13. 6,7,8-trimethoxy-1-bromomethyl-3,4-dihydro-1H-2-benzothiopyran,

14. 8-methoxy-3-phenyl-1-bromomethyl-3,4-dihydro-1H-2-benzothiopyran,

15. 6-hydroxy-4-bromo-1-bromomethyl-3,4-dihydro-1H-2-benzothiopyran,

16.6,7-dimethoxy-4,4-dimethyl-1-bromomethyl-3,4-dihydro-1H-2-benzothiopyran,

17.6,7-dimethoxy-3,3-dimethyl-1-bromomethyl-3,4-dihydro-1H-2-benzothiopyran,

18.1-(bromomethyl)-6,7-dimethoxyspiro[1H-2-benzothiopyran-4(3H),1'-cyclopentane],

19.5-bromomethyl-7,8-dipropoxy-2,3,3a,5,9b-pentahydro-1H-benzo[c]cyclopent[e]thiopyran,

20.3-cyclopentyl-7,8-dimethoxy-1-bromomethyl-3,4-dihydro-1H-2-benzothiopyran,

21.6,7-dihydroxy-4-n-propyl-1-bromomethyl-3,4-dihydro-1H-2-benzothiopyran,

22.6,7-dimethoxy-8-trifluoromethyl-1-bromomethyl-3,4-dihydro-1H-2-benzothiopyran.

Preparation 3 1-(3-chloropropyl)-6,7-dimethoxy-1-methyl-isochroman

A mixture of 3,4-dimethoxyphenylethyl alcohol (1.72 g, 0.01 mole),5-chloro-2-pentanone ethylene ketal (1.64 g, 0.01 mole) and 0.5 ml ofBF₃ etherate in 20 ml of nitromethane is stirred at room temperatureunder N₂ for 4 hours. The reaction mixture is then poured into coldwater and extracted with CH₂ Cl₂. The CH₂ Cl₂ solution is washed withwater, dried (Na₂ SO₄) and concentrated to an oil. The oil ischromatographed on silica gel with 10% ethylacetate/Skellysolve B aseluate to give 40 g (54% yield) of1-(3-chloropropyl)-6,7-dimethoxy-1-methyl-isochroman as a whitecrystalline product, m.p. 77°-79° C. The nmr of the product isconsistent with the structure.

Following the procedure of Preparation 3, but substituting theappropriate alcohol for 3,4-dimethoxyphenethyl alcohol, the1-(3-chloropropyl)-1-methylisochromans of Table 3 can be prepared.

TABLE 3

1. 8-methoxy-7-n-propyl-1-methyl-1-(3-chloropropyl)isochroman,

2. 8-methoxy-1-methyl-1-(3-chloropropyl)isochroman,

3. 5,6-dimethoxy-1-methyl-1-(3-chloropropyl)isochroman,

4. 6-ethoxy-1-methyl-1-(3-chloropropyl)isochroman,

5. 6,7,8-trimethoxy-1-methyl-1-(3-chloropropyl)isochroman,

6. 6-hydroxy-1-methyl-1-(3-chloropropyl)isochroman,

7. 6-methoxy-7-bromo-1-methyl-1-(3-chloropropyl)isochroman,

8. 6-methoxy-7,8-dichloro-1-methyl-1-(3-chloropropyl)isochroman,

9. 6-methoxy-7-trifluoromethyl-1-methyl-1-(3-chloropropyl)isochroman,

10. 6,7-methylenedioxy-1-methyl-1-(3-chloropropyl)isochroman,

11. 6-methoxy-4-methyl-1-methyl-1-(3-chloropropyl)isochroman,

12. 6,8-dimethoxy-3,4-dimethyl-1-methyl-1-(3-chloropropyl)isochroman,

13. 6,7,8-trimethoxy-1-methyl-1-(3-chloropropyl)isochroman,

14. 8-methoxy-3-phenyl-1-methyl-1-(3-chloropropyl)isochroman,

15. 6-hydroxy-4-bromo-1-methyl-1-(3-chloropropyl)isochroman,

16. 6,7-dimethoxy-4,4-dimethyl-1-methyl-1-(3-chloropropyl)isochroman,

17. 6,7-dimethoxy-3,3-dimethyl-1-methyl-1-(3-chloropropyl)isochroman,

18.1-methyl-1-(3-chloropropyl)-6,7-dimethoxyspiro[1H-2-benzopyran-4(3H),1'-cyclopentane],

19.5-methyl-5-(3-chloropropyl)-7,8-dipropoxy-2,3,3a,5,9b-pentahydro-1H-benzo[c]cyclopent[e]pyran,

20. 3-cyclopentyl-7,8-dimethoxy-1-methyl-1-(3-chloropropyl)isochroman,

21. 6,7-dihydroxy-4-n-propyl-1-methyl-1-(3-chloropropyl)isochroman,

22.6,7-dimethoxy-8-trifluoromethyl-1-methyl-1-(3-chloropropyl)isochroman.

Preparation 3A1-(3-Chloropropyl)-3,4-dihydro-6,7-dimethoxy-1-methyl-1H-2-benzothiopyran

A mixture of 3,4-dimethoxyphenylethanethiol, 5-chloro-2-pentanoneethylene ketal and BF₃ etherate in nitromethane is stirred under N₂. Thereaction mixture is then poured into cold water and extracted with CH₂Cl₂. The CH₂ Cl₂ solution is washed with water, dried, (Na₂ SO₄) andconcentrated. Column chromatography of the concentrate gives1-(3-chloropropyl)-3,4-dihydro-6,7-dimethoxy-1-methyl-1H-2-benzothiopyran.

Following the procedure of Preparation 3A, but substituting theappropriate thiol for 3,4-dimethoxyphenylethanethiol, the1-(3-chloropropyl)-3,4-dihydro-6,7-dimethoxy-1-methyl-1H-2-benzothiopyransof Table 3A can be prepared.

TABLE 3A

1.8-methoxy-7-n-propyl-1-(3-chloropropyl)-1-methyl-3,4-dihydro-1H-2-benzothiopyran,

2.8-methoxy-1-(3-chloropropyl)-1-methyl-3,4-dihydro-1H-2-benzothiopyran,

3.5,6-dimethoxy-1-(3-chloropropyl)-1-methyl-3,4-dihydro-1H-2-benzothiopyran,

4. 6-ethoxy-1-(3-chloropropyl)-1-methyl-3,4-dihydro-1H-2-benzothiopyran,

5.6,7,8-trimethoxy-1-(3-chloropropyl)-1-methyl-3,4-dihydro-1H-2-benzothiopyran,

6.6-hydroxy-1-(3-chloropropyl)-1-methyl-3,4-dihydro-1H-2-benzothiopyran,

7.6-methoxy-7-bromo-1-(3-chloropropyl)-1-methyl-3,4-dihydro-1H-2-benzothiopyran,

8.6-methoxy-7,8-dichloro-1-(3-chloropropyl)-1-methyl-3,4-dihydro-1H-2-benzothiopyran,

9.6-methoxy-7-trifluoromethyl-1-(3-chloropropyl)-1-methyl-3,4-dihydro-1H-2-benzothiopyran,

10.6,7-methylenedioxy-1-(3-chloropropyl)-1-methyl-3,4-dihydro-1H-2-benzothiopyran,

11.6-methoxy-4-methyl-1-(3-chloropropyl)-1-methyl-3,4-dihydro-1H-2-benzothiopyran,

12.6,8-dimethoxy-3,4-dimethyl-1-(3-chloropropyl)-1-methyl-3,4-dihydro-1H-2-benzothiopyran,

13.6,7,8-trimethoxy-1-(3-chloropropyl)-1-methyl-3,4-dihydro-1H-2-benzothiopyran,

14.8-methoxy-3-phenyl-1-(3-chloropropyl)-1-methyl-3,4-dihydro-1H-2-benzothiopyran,

15.6-hydroxy-4-bromo-1-(3-chloropropyl)-1-methyl-3,4-dihydro-1H-2-benzothiopyran,

16.6,7-dimethoxy-4,4-dimethyl-1-(3-chloropropyl)-1-methyl-3,4-dihydro-1H-2-benzothiopyran,

17.6,7-dimethoxy-3,3-dimethyl-1-(3-chloropropyl)-1-methyl-3,4-dihydro-1H-2-benzothiopyran,

18.1-methyl-1-(3-chloropropyl)-6,7-dimethoxyspiro[1H-2-benzothiopyran-4(3H),1'-cyclopentane,

19.1-methyl-1-(3-chloropropyl)-7,8-dipropoxy-2,3,3a,5,9b-pentahydro-1H-benzo[c]cyclopent[e]thiopyran,

20.3-cyclopentyl-7,8-dimethoxy-1-methyl-1-(3-chloropropyl)-3,4-dihydro-1H-2-benzothiopyran,

21.6,7-dihydroxy-4-n-propyl-1-(3-chloropropyl)-1-methyl-3,4-dihydro-1H-2-benzothiopyran,

22.6,7-dimethoxy-8-trifluoromethyl-1-(3-chloropropyl)-1-methyl-3,4-dihydro-1H-2-benzothiopyran.

Preparation 4

Following the procedures of Preparations 1-3 but substituting theappropriate halo-substituted ketone or aldehydes from Table 4' thefollowing 1-halo-alkyl benzexepins wherein the alkyl group is a branchedchain or (CH₂)₃ to ₅ can be prepared from3-(3,4-dimethoxyphenyl)propanol.

TABLE 4

1. 7,8-dimethoxy-1-[5-bromopentyl]-1,3,4-tetrahydro-2-benzoxepin,

2. 7,8-dimethoxy-1-[4-chlorobutyl]-1,3,4,5-tetrahydro-2-benzoxepin,

3. 7,8-dimethoxy-1-[3-chloropropyl]-1,3,4,5-tetrahydro-2-benzoxepin,

4.7,8-dimethoxy-1-[1-methyl-3-chloropropyl]-1,3,4,5-tetrahydro-2-benzoxepin,

5.7,8-dimethoxy-1-[2,2-dimethyl-3-bromopropyl]-1,3,4,5-tetrahydro-2-benzoxepin,

6.7,8-dimethoxy-1-[1-ethyl-4-chlorobutyl]-1,3,4,5-tetrahydro-2-benzoxepin,

7.7,8-dimethoxy-1-[1,4-dimethyl-5-bromopentyl]-1,3,4,5-tetrahydro-2-benzoxepin,

8.7,8-dimethoxy-1-[5-bromopentyl]-1-methyl-1,3,4,5-tetrahydro-2-benzoxepin,

9.7,8-dimethoxy-1-[4-chlorobutyl]-1-methyl-1,3,4,5-tetrahydro-2-benzoxepin,

10.7,8-dimethoxy-1-[3-chloropropyl]-1-methyl-1,3,4,5-tetrahydro-2-benzoxepin,

11.7,8-dimethoxy-1-[methyl-3-chloropropyl]-1-methyl-1,3,4,5-tetrahydro-2-benzoxepin,

12.7,8-dimethoxy-1-[2,2-dimethyl-3-bromopropyl]-1-methyl-1,3,4,5-tetrahydro-2-benzoxepin,

13.7,8-dimethoxy-1-[1-ethyl-4-chlorobutyl]-methyl-1,3,4,5-tetrahydro-2-benzoxepin,

14.7,8-dimethoxy-1-[1,4-dimethyl-5-bromopenyl]-methyl-1,3,4,5-tetrahydro-2-benzoxepin,

15.7,8-dimethoxy-1-[5-bromopentyl]-1-(4'-fluorophenyl)-1,3,4,5-tetrahydro-2-benzoxepin,

16.7,8-dimethoxy-1-[4-chlorobutyl]-1-(4'-fluorophenyl)-1,3,4,5-tetrahydro-2-benzoxepin,

17.7,8-dimethoxy-1-[3-chloropropyl]-1-(4'-fluorophenyl)-1,3,4,5-tetrahydro-2-benzoxepin,

18.7,8-dimethoxy-1-[1-methyl-3-chloropropyl]-1-(4'-fluorophenyl)-1,3,4,5-tetrahydro-2-benzoxepin,

19.7,8-dimethoxy-1-[2,2-dimethyl-3-bromopropyl]-1-(4'-fluorophenyl)-1,3,4,5-tetrahydro-2-benzoxepin,

20.7,8-dimethoxy-1-[1-ethyl-4-chlorobutyl]-1-(4'-fluorophenyl)-1,3,4,5-tetrahydro-2-benzoxepin,

21.7,8-dimethoxy-1-[1,4-dimethyl-5-bromopentyl]-1-(4'-fluorophenyl)-1,3,4,5-tetrahydro-2-benzoxepin,

The compounds of Table 4 are derived from the aldehyde or ketones ofTable 4' and 3-(3,4-dimethoxy phenyl)propanol.

TABLE 4'

1. methyl 5-bromopentyl ketone,

2. methyl 4-chlorobutyl ketone,

3. methyl 3-chloropropyl ketone,

4. 6-bromohexanal,

5. 5-chloropentanal,

6. 4-chlorobutanal,

7. p-fluorophenyl 5-bromopentyl ketone,

8. p-fluorophenyl 4-chlorobutyl ketone,

9. p-fluorophenyl 3-chloropropyl ketone,

10. 2-methyl-4-chlorobutanol,

11. 3,3-dimethyl-4-bromobutanol,

12. 2-ethyl-5-chloropentanal,

13. 2,5-dimethyl-6-bromohexanal,

14. methyl(1-methyl-3-chloropropyl ketone,

15. methyl 2,2-dimethyl-3-bromopropyl ketone,

16. methyl 1-ethyl-4-chlorobutyl ketone,

17. methyl 1,4-dimethyl-5-bromopentyl ketone,

18. p-fluorophenyl 1-methyl-3-chloropropyl ketone,

19. p-fluorophenyl 2,2-dimethyl-3-bromopropyl ketone,

20. p-fluorophenyl 1-ethyl-4-chlorobutyl ketone,

21. p-fluorophenyl 1,4-dimethyl-5-bromopentyl ketone,

Similarly, from the alcohols which were used to prepare the benzoxepinsof Table 1 and the appropriate halo substituted ketones or aldehydes(Table 4') and following the procedures of Preparation 1-3 thebenzoxepins which are analogous to those of Table 4 can be prepared.

Preparation 4a

Following the procedures of Preparations 1a to 3a, and 2c, butsubstituting the appropriate halo-substituted ketone or aldehyde, thefollowing halo-alkyl benzothiepins, wherein the alkyl group is abranched chain or (CH₂)₃ to ₅ can be prepared from3-(3,4-dimethoxyphenyl)-1-propanethiol (Table 4a).

TABLE 4a

1. 7,8-dimethoxy-1-[5-bromopentyl]-1,3,4,5-tetrahydro-2-benzothiepin,

2. 7,8-dimethoxy-1-[4-chlorobutyl]-1,3,4,5-tetrahydro-2-benzothiepin,

3. 7,8-dimethoxy-1-[3-chloropropyl]-1,3,4,5-tetrahydro-2-benzothiepin,

4. 7,8-dimethoxy-1-[1-methyl-3-chloropropyl]-tetrahydro-2-benzothiepin,

5.7,8-dimethoxy-1-[2,2-dimethyl-3-bromopropyl]-1,3,4,5-tetrahydro-2-benzothiepin,

6.7,8-dimethoxy-1-[1-ethyl-4-chlorobutyl]-1,3,4,5-tetrahydro-2-benzothiepin,

7.7,8-dimethoxy-1-[1,4-dimethyl-5-bromopentyl]-1,3,4,5-tetrahydro-2-benzothiepin,

8.7,8-dimethoxy-1-[5-bromopentyl]-1-methyl-1,3,4,5-tetrahydro-2-benzothiepin

9.7,8-dimethoxy-1-[4-chlorobutyl]-1-methyl-1,3,4,5-tetrahydro-2-benzothiepin

10.7,8-dimethoxy-1-[3-chloropropyl]-1-methyl-1,3,4,5-tetrahydro-2-benzothiepin,

11.7,8-dimethoxy-1-[1-methyl-3-chloropropyl]-1-methyl-1,3,4,5-tetrahydro-2-benzothiepin,

12.7,8-dimethoxy-1-[2,2-dimethyl-3-bromopropyl]-1-methyl-1,3,4,5-tetrahydro-2-benzothiepin,

13.7,8-dimethoxy-1-[1-ethyl-4-chlorobutyl]-1-methyl-1,3,4,5-tetrahydro-2-benzothiepin,

14.7,8-dimethoxy-1-[1,4-dimethyl-5-bromopentyl]-1-methyl-1,3,4,5-tetrahydro-2-benzothiepin,

15.7,8-dimethoxy-1-[5-bromopentyl]-1-(4'-fluorophenyl)-1,3,4,5-tetrahydro-2-benzothiepin,

16.7,8-dimethoxy-1-[4-chlorobutyl]-1-[4'-fluorophenyl)-1,3,4,5-tetrahydro-2-benzothiepin,

17.7,8-dimethoxy-1-[3-chloropropyl]-1-(4'-fluorophenyl)-1,3,4,5-tetrahydro-2-benzothiepin,

18.7,8-dimethoxy-1-[1-methyl-3-chloropropyl]-1-(4'-fluorophenyl)-1,3,4,5-tetrahydro-2-benzothiepin,

19.7,8-dimethoxy-1-[2,2-dimethyl-3-bromopropyl]-1-(4'-fluorophenyl)-1,3,4,5-tetrahydro-2-benzothiepin,

20.7,8-dimethoxy-1-[1-ethyl-4-chlorobutyl]-1-(4'-fluorophenyl)-1,3,4,5-tetahydro-2-benzothiepin,

21.7,8-dimethoxy-1-[1,4-dimethyl-5-bromopentyl]-1-4'-fluorophenyl)-1,3,4,5-tetrahydro-2-benzothiepin,

Similarly, from the thiols from Table 1' and the appropriate substitutedketones or aldehydes of Table 4' and following the procedures ofPreparation 1a-3a the benzothiepins which are analogous to those ofTable 4a can be prepared.

Preparation 4b

Following the procedures of Preparations 2, 2b, and 3 but substitutingthe appropriate halo-substituted ketones or aldehydes from Table 4', thefollowing 1-haloalkyl isochromans wherein the alkyl group is a branchedchain or (CH₂)₃ to ₅ can be prepared from 3-(3,4-dimethoxyphenyl)ethanol (Table 4b).

TABLE 4b

1. 6,7-dimethoxy-1-[5-bromopentyl]isochroman,

2. 6,7-dimethoxy-1-[4-chlorobutyl]isochroman,

3. 6,7-dimethoxy-1-[3-chloropropyl]isochroman,

4. 6,7-dimethoxy-1-[1-methyl-3-chloropropyl]isochroman,

5. 6,7-dimethoxy-1-[2,2-dimethyl-3-bromopropyl]isochroman,

6. 6,7-dimethoxy-1-[1-ethyl-4-chlorobutyl]isochroman,

7. 6,7-dimethoxy-1-[5-bromopentyl]isochroman,

8. 6,7-dimethoxy-1-methyl-1-[5-bromopentyl]isochroman,

9. 6,7-dimethoxy-1-[4-chlorobutyl]-1-methylisochroman,

10. 6,7-dimethoxy-1-[3-chloropropyl]-1-methylisochroman,

11. 6,7-dimethoxy-1-[1-methyl-3-chloropropyl]-1-methylisochroman,

12. 6,7-dimethoxy-1-[2,2-dimethyl-3-bromopropyl]-1-methylisochroman,

13. 6,7-dimethoxy-1-[1-ethyl-4-chlorobutyl]-1-methylisochroman,

14. 6,7-dimethoxy-1-[1,4-dimethyl-5-bromopentyl]-1-methylisochroman,

15. 6,7-dimethoxy-1-[5-bromopentyl]-1-(4'-fluorophenyl)isochroman,

16. 6,7-dimethoxy-1-[4-chlorobutyl]-1-(4'-fluorophenyl)isochroman,

17. 6,7-dimethoxy-1-[3-chloropropyl]-1-(4'-fluorophenyl)isochroman,

18.6,7-dimethoxy-1-[1-methyl-3-chloropropyl]-1-(4'-fluorophenyl)isochroman,

19.6,7-dimethyl-[2,2-dimethyl-3-bromopropyl]-1-(4'-fluorophenyl)isochroman,

20.6,7-dimethoxy-1-[1-ethyl-4-chlorobutyl]-1-(4'-fluorophenyl)isochroman,

21.6,7-dimethoxy-1-[1,4-dimethyl-5-bromopentyl]-1-(4'-fluorophenyl)isochroman.

Similarly, from the alcohols which were used to prepare the isochromansof Tables 2, 2b, and 3 and the appropriate halo substituted ketones oraldehydes from Table 4', and following the procedures of Preparations 2,2b, and 3 the isochromans which are analogous to those of Table 4b canbe prepared.

Preparation 4c

Following the procedures of preparations 2a, 2c, and 3a but substitutingthe appropriate halo-substituted ketones or aldehydes from Table 4', thefollowing 1-haloalkyl-3,4-dihydro-1H-2-benzothiopyrans wherein the alkylgroup is a branched chain or (CH₂)₃ to 5 can be prepared from2-(3,4-dimethoxyphenyl)ethanethiol (Table 4c).

TABLE 4c

1. 6,7-dimethoxy-1-(5-bromopentyl)-3,4-dihydro-1H-2-benzothiopyran,

2. 6,7-dimethoxy-1-(4-chlorobutyl)-3,4-dihydro-1H-2-benzothiopyran,

3. 6,7-dimethoxy-1-(3-chloropropyl)-3,4-dihydro-1H-2-benzothiopyran,

4.6,7-dimethoxy-1-(1-methyl-3-chloropropyl)-3,4-dihydro-1H-2-benzothiopyran,

5.6,7-dimethoxy-1-(2,2-dimethyl-3-bromopropyl)-3,4-dihydro-1H-2-benzothiopyran,

6.6,7-dimethoxy-1-(1-ethyl-4-chloropropyl)-3,4-dihydro-1H-2-benzothiopyran,

7.6,7-dimethoxy-1-(1,4-dimethyl-5-bromopentyl)-3,4-dihydro-1H-2-benzothipyran,

8.6,7-dimethoxy-1-(5-bromopentyl)-1-methyl-3,4-dihydro-1H-2-benzothiopyran,

9.6,7-dimethoxy-1-(4-chlorobutyl)-1-methyl-3,4-dihydro-1H-2-benzothiopyran,

10.6,7-dimethoxy-1-(3-chloropropyl)-1-methyl-3,4-dihydro-1H-2-benzothiopyran,

11.6,7-dimethoxy-1-(1-methyl-3-chloropropyl)-1-methyl-3,4-dihydro-1H-2-benozhiopyran,

12.6,7-dimethoxy-1-(2,2-dimethyl-5-bromopentyl)-1-methyl-3,4-dihydro-1H-2-benzothiopyran,

13.6,7-dimethoxy-1-(1-ethyl-4-chlorobutyl)-1-methyl-3,4-dihydro-1H-2-benzothiopyran,

14.6,7-dimethoxy-1-(1,4-dimethyl-5-bromopentyl)-1-methyl-3,4-dihydro-1H-2-benzothiopyran,

15.6,7-dimethoxy-1-(5-bromopentyl)-1-(4'-fluorophenyl)-1-methyl-3,4-dihydro-1H-2-benzothiopyran,

16.6,7-dimethoxy-1-(4-chlorobutyl)-1-methyl-3,4-dihydro-1H-2-benzothiopyran,

17.6,7-dimethoxy-1-(3-chloropropyl)-1-methyl-3,4-dihydro-1H-2-benzothiopyran,

18.6,7-dimethoxy-1-(1-methyl-3-chloropropyl)-1-methyl-3,4-dihydro-1H-2-benzothiopyran,

19.6,7-dimethoxy-1-(2,2-dimethyl-3-bromopropyl)-1-methyl-3,4-dihydro-1H-2-benzothiopyran,

20.6,7-dimethoxy-1-(1-ethyl-4-chlorobutyl)-1-methyl-3,4-dihydro-1H-2-benozthiopyran,

21.6,7-dimethoxy-1-(1,4-dimethyl-5-bromopentyl)-1-methyl-3,4-dihydro-1H-2-benzothiopyran.

Similarly, from the thiols from Table 2' and the appropriate substitutedketones or aldehydes of Table 4' and following the procedures ofPreparation 2a, 2c, and 3a the benzothiopyrans which are analogous tothose of Table 4a can be prepared.

Preparation 52-[(1,3,4,5-Tetrahydro-7,8-dimethoxy-2-benzoxein-1-yl)methoxy]ethylchloride

A mixture of 10.33 g (0.343 moles) of1-bromomethyl-1,3,4,5-tetrahydro-7,8-dimethoxy-2-benzoxepin, 10 ml of2-chloroethanol, and 6.77 g of barium carbonate is stirred at 90° for 46hours. The reaction mixture is then cooled, ethanol is added, and thesolids are removed by filtration. The filtrate is taken to dryness invacuo and the resulting oil is extracted with methylene chloride andaqueous sodium bicarbonate. The organic layer is then taken to drynessand chromatographed on silica gel using 10% ethylacetate:Skellysolve Bas eluent to give 4.18 g (41%) of2-[(1,3,4,5-tetrahydro-7,8-dimethoxy-2-benzoxepin-1-yl)methoxy]ethylchloride, m.p. 90°-91°.

Analysis Calc'd for: C₁₅ H₂₁ ClO₄ : C, 59.89; H, 7.04. Found: C, 60.06;H, 7.57.

Following the procedure of Preparation 5, but substituting theappropriate 1-bromomethyl 2-benzoxepin from Table 1 for1-bromomethyl-7,8-dimethoxybenzoxepin and chloroethanol the2-[(1,3,4,5-tetrahydro-2-benzoxepin-1-yl)methoxy]ethyl chlorides ofTable 5 can be prepared.

TABLE 5

1.2-[(9-methoxy-8-propyl-1,3,4,5-tetrahydro-2-benzoxepin-1-yl)methoxy]ethylchloride,

2. 2-[(2-methoxy-1,3,4,5-tetrahydro-2-benzoxepin-1-yl)methoxy]ethylchloride,

3. 2-[(6,7-dimethoxy-1,3,4,5-tetrahydro-2-benzoxepin-1-yl)methoxy]ethylchloride,

4. 2-[(7-ethoxy-1,3,4,5-tetrahydro-2-benzoxepin-1-yl)methoxy]ethylchloride,

5.2-[(7,8,9-trimethoxy-1,3,4,5-tetrahydro-2-benzoxepin-1-yl)methoxy]ethylchloride,

6.2-[(7-hydroxy-6-methoxy-1,3,4,5-tetrahydro-2-benzoxepin-1-yl)methoxy]ethylchloride,

7.2-[(8-bromo-7-methoxy-1,3,4,5-tetrahydro-2-benzoxepin-1-yl)methoxy]ethylchloride,

8.2-[(7-methoxy-8,9-dichloro-1,3,4,5-tetrahydro-2-benzoxepin-1-yl)methoxy]ethylchloride,

9.2-[(7-methoxy-8-trifluoromethyl-1,3,4,5-tetrahydro-2-benzoxepin-1-yl)methoxy]ethylchloride,

10.2-[(7,8-methylenedioxy-1,3,4,5-tetrahydro-2-benzoxepin-1-yl)methoxy]ethylchloride,

11.2-[(7-methoxy-5-methyl-1,3,4,5-tetrahydro-2-benzoxepin-1-yl)methoxy]ethylchloride,

12.2-[(7,9-dimethoxy-4,5-dimethyl-1,3,4,5-tetrahydro-2-benzoxepin-1-yl)methoxy]ethylchloride, 13.2-[(7,8,9-trimethoxy-4-methyl-1,3,4,5-tetrahydro-2-benzoxepin-1-yl)methoxy]ethylchloride,

14.2-[(9-methoxy-4-phenyl-1,3,4,5-tetrahydro-2-benzoxepin-1-yl)methoxy]ethylchloride, 15.2-[(7-hydroxy-5-bromo-1,3,4,5-tetrahydro-2-benzoxepin-1-yl)methoxy]ethylchloride,

16.2-[(7,8-dimethoxy-5,5-dimethyl-1,3,4,5-tetrahydro-2-benzoxepin-1-yl)methoxy]ethylchloride,

17.2-[(7,8-dimethoxy-4,4-dimethyl-1,3,4,5-tetrahydro-2-benzoxepin-1-yl)methoxy]ethylchloride,

18.1-(2-chloromethoxymethyl)-1,5-dihydro-7,8-dimethoxyspiro[2-benzoxepin-4(3H),1'-cyclopentane],

19. 6-(2-chloroethoxymethyl)-8,9-dipropoxy-2,3,3a,4,6,10b-hexahydro-1H-benzo[c]cyclopent[e]oxepin,

20.2-[(4-chloropentyl-8,9-dimethoxy-1,3,4,5-tetrahydro-2-benzoxepin-1-yl)methoxy]ethylchloride,

21.2-[(7,8-dihydroxy-5-propyl-1,3,4,5-tetrahydro-2-benzoxepin-1-yl)methoxy]ethylchloride,

22.2-[(7,8-dimethoxy-9-trifluoromethyl-1,3,4,5-tetrahydro-2-benzoxepin-1-yl)methoxy]ethylchloride.

Similarly from chloroethanol and the appropriate1-chloroethylbenzoxepins of Table 1b or the 1-chloropropylbenzoxepins ofTable 3a, and following the procedures of preparation 5, the analogous2-[(1,3,4,5-tetrahydro-2-benzoxepin-1-yl)alkoxy]ethyl chlorides can beprepared.

Preparation 5a2-[(1,3,4,5-tetrahydro-7,8-dimethoxy-2-benzothiepin-1-yl)methoxy]ethylchloride

A mixture of 1-bromomethyl-7,8-dimethoxybenzothiepin 2-chloroethanol,and barium carbonate is stirred at 40°-90° for 10-60 hours. The reactionmixture is then cooled, ethanol is added, and the solids are removed byfiltration. The filtrate is taken to dryness in vacuo and the resultingoil is extracted with methylene chloride and aqueous sodium bicarbonate.The organic layer is then taken to dryness and chromatographed on silicagel to give2-[(1,3,4,5-tetrahydro-7,8-dimethoxy-2-benzothiepin-1-yl)methoxy]ethylchloride.

Following the procedure of Preparation 5a, but substituting theappropriate 1-haloalkyl-benzothiepin for1-bromomethyl-7,8-dimethoxybenzoxepin the2-[(1,3,4,5-tetrahydro-2-benzothiepin-1-yl)alkoxy]ethyl halides (inTable 5a) can be prepared.

TABLE 5a

1.2-[(9-methoxy-8-propyl-1,3,4,5-tetrahydro-2-benzothiepin-1-yl)methoxy]ethylchloride,

2. 2-[(9-methoxy-1,3,4,5-tetrahydro-2-benzothiepin-1-yl)methoxy]ethylchloride,

3.2-[(6,7-dimethoxy-1,3,4,5-tetrahydro-2-benzothiepin-1-yl)methoxy]ethylchloride,

4. 2-[(7-ethoxy-1,3,4,5-tetrahydro-2-benzothiepin-1-yl)methoxy]ethylchloride,

5.2-[(7,8,9-trimethoxy-1,3,4,5-tetrahydro-2-benzothiepin-1-yl)methoxy]ethylchloride,

6.2-[(7-hydroxy-6-methoxy-1,3,4,5-tetrahydro-2-benzothiepin-1-yl)methoxy]ethylchloride,

7.2-[(8-bromo-7-methoxy-1,3,4,5-tetrahydro-2-benzothiepin-1-yl)methoxy]ethylchloride,

8.2-[(7-methoxy-8,9-dichloro-1,3,4,5-tetrahydro-2-benzothiepin-1-yl)methoxy]ethylchloride,

9.2-[(7-methoxy-8-trifluoromethyl-1,3,4,5-tetrahydro-2-benzothiepin-1-yl)methoxy]ethylchloride,

10.2-[(7,8-mehylenedioxy-1,3,4,5-tetrahydro-2-benzothiepin-1-yl)mdthoxy]ethylchloride,

11.2-[(7-methoxy-5-methyl-1,3,4,5-tetrahydro-2-benzothiepin-1-yl)methoxy]ethylchloride,

12.2-[(7,9-dimethoxy-4,5-dimethyl-1,3,4,5-tetrahydro-2-benzothiepin-1-yl)methoxy]ethylchloride, 13.2-[(7,8,9-trimethoxy-4-methyl-1,3,4,5-tetrahydro-2-benzothiepin-1-yl)methoxy]ethylchloride,

14.2-[(9-methoxy-4-phenyl-1,3,4,5-tetrahydro-2-benzothiepin-1-yl)methoxy]ethylchloride.

15.2-[(7-hydroxy-5-bromo-1,3,4,5-tetrahydro-2-benzothiepin-1-yl)methoxy]ethylchloride,

16.2-[(7,8-dimethoxy-5,5-dimethyl-1,3,4,5-tetrahydro-2-benzothiepin-1-yl)methoxy]ethylchloride,

17.2-[(7,8-dimethoxy-4,4-dimethyl-1,3,4,5-tetrahydro-2-benzothiepin-1-yl)methoxy]ethylchloride,

18.1-(2-chloroethoxymethyl)-1,5-dihydro-7,8-dimethoxyspiro[2-benzothiepin-4(3H),1'-cyclopentane],

19. 6-(2-chloroethoxymethyl)-8,9-dipropoxy-2,3,3a,4,6,10b-hexahydro-1H-benzo[c]cyclopent[e]thiepin,

20.2-[(4-cyclopenyl-8,9-dimethoxy-1,3,4,5-tetrahydro-2-benzothiepin-1-yl)methoxy]ethylchloride,

21.2-[(7,8-dihydroxy-5-propyl-1,3,4,5-tetrahydro-2-benzothiepin-1-yl)methoxy]ethylchloride,

22.2-[(7,8-dimethoxy-9-trifluoromethyl-1,3,4,5-tetrahydro-2-benzothiepin-1-yl)methoxy]ethylchloride.

Similarly, from chloroethanol and the appropriate1-chloroethylbenzothiepins of Table 1B or the1-chloropropylbenzothiepins of Table 3, and following the procedure ofpreparation 5, the corresponding2-[(1,3,4,5-tetrahydro-2-benzothiepin-1-yl)alkoxy]ethyl chlorides can beprepared.

Preparation 62-[(1,3,4,5-Tetrahydro-7,8-dimethoxy-2-benzoxepin-1-yl)methoxy]ethanol

A mixture of 3.67 g (12.2 mmoles) of1-bromomethyl-7,8-dimethoxy-2-benzoxepin, 2.12 ml (12.2 mmoles) ofdiisopropylethylamine, and 15 ml of ethylene glycol is heated at 100°for 7 hours. The reaction mixture is then cooled and extracted withmethylene chloride, then with water and finally with brine. The organiclayer is filtered through Na₂ SO₄, taken to dryness, and chromatographedon silica gel to give 3.06 g (89%) of2-[(1,3,4,5-tetrahydro-7,8-dimethoxy-2-benzoxepin-1-yl)methoxy]ethanol:mass spectrum: M⁺ (m/e=282).

Following the procedure of Preparation 6, but substituting theappropriate 1-halomethyl-2-benzoxepin, the2-[(1,3,4,5-tetrahydro-2-benzoxepin-1-yl)methoxy]ethanols of Table 6 canbe prepared.

TABLE 6

1.2-[(1,3,4,5-tetrahydro-9-methoxy-8-propyl-2-benzoxepin-1-yl)methoxy]ethanol,

2. 2-[(1,3,4,5-tetrahydro-9-methoxy-2-benzoxepin-1-yl)methoxy]ethanol,

3.2-[(1,3,4,5-tetrahydro-6,7-dimethoxy-2-benzoxepin-1-yl)methoxy]ethanol,

4. 2-[(1,3,4,5-tetrahydro-7-ethoxy-2-benzoxepin-1-yl)methoxy]ethanol,

5.2-[(1,3,4,5-tetrahydro-7,8,9-trimethoxy-2-benzoxepin-1-yl)methoxy]ethanol,

6.2-[(1,3,4,5-tetrahydro-7-hydroxy-6-methoxy-2-benzoxepin-1-yl)methoxy]ethanol,

7.2-[(1,3,4,5-tetrahydro-8-bromo-7-methoxy-2-benzoxepin-1-yl)methoxy]ethanol

8.2-[(1,3,4,5-tetrahydro-7-methoxy-8,9-dichloro-2-benzoxepin-1-yl)methoxy]ethanol,

9.2-[(1,3,4,5-tetrahydro-7-methoxy-8-trifluoromethyl-2-benzoxepin-1-yl)methoxy]ethanol,

10.2-[(1,3,4,5-tetrahydro-7,8-methylenedioxy]-2-benzoxepin-1-yl)methoxy]ethanol,

11.2-[(1,3,4,5-tetrahydro-7-methoxy-5-methyl-2-benzoxepin-1-yl)methoxy]ethanol

12.2-[(1,3,4,5-tetrahydro-7,9-dimethoxy-4,5-dimethyl-2-benzoxepin-1-yl)methoxy]ethanol

13.2-[(1,3,4,5-tetrahydro-7,8,9-trimethoxy-4-methyl-2-benzoxepin-1-yl)methoxy]ethanol

14.2-[(1,3,4,5-tetrahydro-9-methoxy-4-phenyl-2-benzoxepin-1-yl)methoxy]ethanol

15.2-[(1,3,4,5-tetrahydro-7-hydroxy-5-bromo-2-benzoxepin-1-yl)methoxy]ethanol

16.2-[(1,3,4,5-tetrahydro-7,8-dimethoxy-5,5-dimethyl-2-benzoxepin-1-yl)methoxy]ethanol

17.2-[(1,3,4,5-tetrahydro-7,8-dimethoxy-4,4-dimethyl-2-benzoxepin-1-yl)methoxy]ethanol

18.2-[[1,5-dihydro-7,8-dimethoxyspiro[2-benzoxepin-4(3H)-1'-cyclopentane]-1-yl]methoxy]ethanol

19.2-[(8,9-dipropoxy-2,3,3a,4,6,10b-hexahydro-1H-benzo[c]cyclopent[e]oxepin-6-yl)methoxy]ethanol

20.2-[(1,3,4,5-tetrahydro-4-cyclopentyl-8,9-dimethoxy-2-benzoxepin-1-yl)methoxy]ethanol

21. 2-[(1,3,4,5-tetrahydro-7,8-dihydroxy-5-npropyl-2-benzoxepin-1-yl)methoxy]ethanol

22.2-[(7,8-dimethoxy-9-trifluoromethyl-1,3,4,5-tetrahydro-2-benzoxepin-1-yl)methoxy]ethanol

Similarly, from ethylene glycol and the appropriate 1-chloroethylbenzoxepins of Table 1B or the 1-chloropropylbenzoxepins of Table 3a,and following the procedure of preparation 5, the analogous2-[(1,3,4,5-tetrahydro-2-benzoxepin-1-yl)alkoxy]ethanols can beprepared.

Preparation 6A2-[(1,3,4,5-tetrahydro-7,8-dimethoxy-2-benzothiepin-1-yl)methoxy]ethanol

A mixture of 1-bromomethyl-7,8-dimethoxy-2-benzothiepin,diisopropylethylamine, and ethylene glycol is heated at 30° to 100° C.for 5-50 hours. The reaction mixture is then cooled, diluted withmethylene chloride and extracted with water followed by brine. Theorganic layer is filtered through Na₂ SO₄, taken to dryness, andchromatograhed on silica gel to give2-[(1,3,4,5-tetrahydro-7,8-dimethoxy-2-benzothiepin-1-yl)methoxy]ethanol.

Following the procedure of Preparation 6A, but substituting theappropriate 1-halomethyl-2-benzothiepin the2-[(1,3,4,5-tetrahydro-2-benzothiepin-1-yl)methoxy]ethanols of Table 6Acan be prepared.

TABLE 6A

1.2-[(1,3,4,5-tetrahydro-8-propyl-9-methoxy-2-benzothiepin-1-yl)methoxy]ethanol

2. 2-[(1,3,4,5-tetrahydro-9-methoxy-2-benzothiepin-yl)methoxy]ethanol

3.2-[(1,3,4,5-tetrahydro-6,7-dimethoxy-2-benzothiepin-1-yl)methoxy]ethanol

4. 2-[(1,3,4,5-tetrahydro-7-ethoxy-2-benzothiepin-1-yl)methoxy]ethanol

5.2-[(1,3,4,5-tetrahydro-7,8,9-trimethoxy-2-benzothiepin-1-yl)methoxy]ethanol

6.2-[(1,3,4,5-tetrahydro-7-hydroxy-6-methoxy-2-benzothiepin-1-yl)methoxy]ethanol

7.2-[(1,3,4,5-tetrahydro-8-bromo-7-methoxy-2-benzothiepin-1-yl)methoxy]ethanol

8.2-[(1,3,4,5-tetrahydro-7-methoxy-8,9-dichloro-2-benzothiepin-1-yl)methoxy]ethanol

9.2-[(1,3,4,5-tetrahydro-7-methoxy-8-trifluoromethyl)-2-benzothiepin-1-yl)methoxy]ethanol

10.2-[(1,3,4,5-tetrahydro-7,8-methylenedioxy-2-benzothiepin-1-yl)methoxy]ethanol

11.1-[(1,3,4,5-tetrahydro-7-methoxy-5-methyl-2-benzothiepin-1-yl)methoxy]ethanol

12.2-[(1,3,4,5-tetrahydro-7,9-dimethoxy-4,5-dimethyl-2-benzothiepin-1-yl)methoxy]ethanol

13.2-[(1,3,4,5-tetrahydro-7,8,9-trimethoxy-4-methyl-2-benzothiepin-1-yl)methoxy]ethanol

14.2-[(1,3,4,5-tetrahydro-9-methoxy-4-phenyl-2-benzothiepin-1-yl)methoxy]ethanol

15.2-[(1,3,4,5-tetrahydro-7-hydroxy-5-bromo-2-benzothiepin-1-yl)methoxy]ethanol

16.2-[(1,3,4,5-tetrahydro-7,8-dimethoxy-5,5-dimethyl-2-benzothiepin-1-yl)methoxy]ethanol

17.2-[(1,3,4,5-tetrahydro-7,8-dimethoxy-4,4-dimethyl-2-benzothiepin-1-yl)methoxy]ethanol

18.2-[1,5-dihydro-7,8-dimethoxyspiro[2-benzothiepin-4(3H)-1'-cyclopentane]-1-yl]methoxyethanol

19.2-[(8,9-dipropoxy-2,3,3a,4,6,10b-hexahydro-1H-benzo[c]cyclopent[e]thiepin-6-yl)methoxy]ethanol

20.2-[(1,3,4,5-tetrahydro-4-cyclopentyl-8,9-dimethoxy-2-benzothiepin-1-yl)methoxy]ethanol

21.2-[(1,3,4,5-tetrahydro-7,8-dihydroxy-5-propyl-2-benzothiepin-1-yl)methoxy]ethanol

22.2-[(7,8-dimethoxy-9-trifluoromethyl-1,3,4,5-tetrahydro-2-benzothiepin-1-yl)methoxy]ethanol

Similarly, from ethylene glycol and the appropriate1-chloroethyl-2-benzothiepins or the 1-chloropropyl-2-benzothiepins ofTable 4A, the analogous2-[(1,3,4,5-tetrahydro-2-benzothiepin-1-yl)alkoxy] ethanols can beprepared with the procedure of Preparation 6A.

Preparation 72-[(1,3,4,5-tetrahydro-7,8-dimethoxy-2-benzoxepin-1-yl)methoxy]ethyl4-nitrobenzene sulfonate

To a mixture of 3.00 g (10.6 mmoles) of2-[(1,3,4,5-tetrahydro-7,8-dimethoxy-2-benzoxepin-1-yl)methoxy]ethanoland 1.63 ml (11.7 mmoles) of triethylamine is added 2.59 g (11.7 mmoles)of p-nitrobenzenesulfonyl chloride. The reaction mixture is stirred atroom temperature for 1 hour and then heated at 50° for 30 minutes. Tothis is added an additional 0.5 g of -nitrobenzenesulfonyl chloride and0.5 ml of triethylamine. After stirring at room temperature for 30minutes, the reaction mixture is extracted with aqueous sodiumbicarbonate and brine. The organic layer is filtered through sodiumsulfate and taken to dryness. The residue is chromatographed on silicagel using 1% methanol methylene chloride as eluant to give 1.56 g (32%)2-[(1,3,4,5-tetrahydro-7,8-dimethoxy-2-benzoxepin-1-yl)methoxy]ethyl4-nitrobenzene sulfonate. The nmr spectrum was consistent with theassigned structure.

Utilizing the procedure of Preparation 7, but substituting theappropriate 2-[(1,3,4,5-tetrahydro-2-benzoxepin-1-yl)methoxy]ethanol,the 2-[(1,3,4,5-tetrahydro-2-benzoxepin-1-yl)methoxy]ethylbenzenesulfonates of Table 7 can be prepared.

TABLE 7

1.2-[(1,3,4,5-tetrahydro-9-methoxy-8-propyl-2-benzoxepin-1-yl)methoxy]ethyl4-nitrobenzenesulfonate

2. 2-[(1,3,4,5-tetrahydro-9-methoxy-2-benzoxepin-1-yl)methoxy]ethyl4-nitrobenzenesulfonate

3. 2-[(1,3,4,5-tetrahydro-6,7-dimethoxy-2-benzoxepin-1-yl)methoxy]ethyl4-methoxybenzenesulfonate

4. 2-[(1,3,4,5-tetrahydro-7-ethoxy-2-benzoxepin-1-yl)methoxy]ethyl4-ethylbenzenesulfonate

5. 2-[(1,3,4-tetrahydro-7,8,9-trimethoxy-2-benzoxepin-1-yl)methoxy]ethyl4-nitrobenzenesulfonate

6.2-[(1,3,4,5-tetrahydro-7-hydroxy-6-methoxy-2-benzoxepin-1-yl)methoxy]ethyl4-chlorobenzenesulfonate

7.2-[(1,3,4,5-tetrahydro-8-bromo-7-methoxy-2-benzoxepin-1-yl)methoxy]ethyl4-nitrobenzenesulfonate

8.2-[(1,3,4,5-tetrahydro-7-methoxy-8,9-dichloro-2-benzoxepin-1-yl)methoxy]ethyl4-nitrobenzenesulfonate

9.2-[(1,3,4,5-tetrahydro-7-methoxy-8-trifluoromethyl)-2-benzoxepin-1-yl)methoxy]ethyl4-bromobenzenesulfonate

10.2-[(1,3,4,5-tetrahydro-7,8-methylenedioxy-2-benzoxepin-1-yl)methoxy]ethyl4-nitrobenzenesulfonate

11.2-[(1,3,4,5-tetrahydro-7-methoxy-5-methyl-2-benzoxepin-1-yl)methoxy]ethyl2-methylbenzenesulfonate

12.2-[(1,3,4,5-tetrahydro-7,9-dimethoxy-4,5-dimethoxy-2-benzoxepin-1-yl)methoxy]ethyl4-nitrobenzenesulfonate

13.2-[(1,3,4,5-tetrahydro-7,8,9-trimethoxy-4-methyl-2-benzoxepin-1-yl)methoxy]ethyl4-nitrobenzenesulfonate

14.2-[(1,3,4,5-tetrahydro-9-methoxy-4-phenyl-2-benzoxepin-1-yl)methoxy]ethyl3-trifluoromethylbenzenesulfonate

15.2-[(1,3,4,5-tetrahydro-7-hydroxy-5-bromo-2-benzoxepin-1-yl)methoxy]ethyl4-nitrobenzenesulfonate

16.2-[(1,3,4,5-tetrahydro-7,8-dimethoxy-5,5-dimethyl-2-benzoxepin-1-yl)methoxy]ethyl4-nitrobenzenesulfonate

17.2-[(1,3,4,5-tetrahydro-7,8-dimethoxy-4,4-dimethyl-2-benzoxepin-1-yl)methoxy]ethyl3-trifluoromethylbenzenesulfonate

18.2-[[1,5-dihydro-7,8-dimethoxyspiro[2-benzoxepin-4(3H)-1'-cyclopentane]-1-yl]methoxy]ethyl4-nitrobenzenesulfonate

19.2-[(8,9-dipropoxy-2,3,3a,4,6,10b-hexahydro-1H-benzo[c]cyclopent[e]oxepin-6-yl)methoxy]ethyl2-ethylbenzenesulfonate

20.2-[(1,3,4,5-tetrahydro-4-cyclopentyl-8,9-dimethoxy-2-benzoxepin-1-yl)methoxy]ethyl4-nitrobenzenesulfonate

21.2-[(1,3,4,5-tetrahydro-7,8-dihydroxy-5-n-propyl-2-benzoxepin-1-yl)methoxy]ethyl4-nitrobenzenesulfonate

22.2-[(1,3,4,5-tetrahydro-7,8-dimethoxy-9-trifluoromethyl-2-benzoxepin-1-yl)methoxy]ethyl 3-nitrobenzenesulfonate

Similarly, from the appropriate2-[(1,3,4,5-tetrahydro-2-benzoxepin-1-yl)ethoxy]ethanol and theappropriately substituted benzenesulfonyl chloride the corresponding2-[(1,3,4,5-tetrahydro-2-benzoxepin-1-yl)ethoxy]ethyl benzenesulfonatescan be prepared using the procedure of Preparation 7.

Preparation 7A2-[(1,3,4,5-tetrahydro-7,8-dimethoxy-2-benzothiepin-1-yl)methoxy]ethyl4-nitrobenzenesulfonate

To a mixture of2-[(1,3,4,5-tetrahydro-7,8-dimethoxy-2-benzothiepn-1-yl)methoxy]ethanoland triethylamine is added p-nitrobenzenesulfonyl chloride. The reactionmixture is stirred at room temperature for 30 minutes. The reactionmixture is then extracted with aqueous sodium bicarbonate and brine. Theorganic layer is filtered through sodium sulfate and taken to dryness.The residue is chromatographed on silica gel to give2-[(1,3,4,5-tetrahydro-7,8-dimethoxy-2-benzothiepin-1-yl)methoxy]ethyl4-nitrobenzenesulfonate.

Utilizing the procedure of Preparation 7A but substituting theappropriate 2-[(1,3,4,5-tetrahydro-2-benzothiepin-1-yl)methoxy]ethanol,the 2-[(1,3,4,5-tetrahydro-2-benzothiepin-1-yl)ethyl benzenesulfonatesof Table 7A can be prepared.

TABLE 7A

1.2-[(1,3,4,5-tetrahydro-9-methoxy-7-propyl-2-benzothiepin-1-yl)methoxy]ethyl4-nitrobenzenesulfonate

2. 2-[(1,3,4,5-tetrahydro-9-methoxy-2-benzothiepin-1-yl)methoxy]ethyl4-nitrobenzenesulfonate

3.2-[(1,3,4,5-tetrahydro-6,7-dimethoxy-2-benzothiepin-1-yl)methoxy]ethyl4-methoxybenzenesulfonate

4. 2-[(1,3,4,5-tetrahydro-7-ethoxy-2-benzothiepin-1-yl)methoxy]ethyl4-ethylbenzenesulfonate

5.2-[(1,3,4,5-tetrahydro-7,8,9-trimethoxy-2-benzothiepin-1-yl)methoxy]ethyl4-nitrobenzenesulfonate

6.2-[(1,3,4,5-tetrahydro-7-hydroxy-6-methoxy-2-benzothiepin-1-yl)methoxy]ethyl4-chlorobenzenesulfonate

7.2-[(1,3,4,5-tetrahydro-8-bromo-7-methoxy-2-benzothiepin-1-yl)methoxy]ethyl4-nitrobenzenesulfonate

8.2-[(1,3,4,5-tetrahydro-7-methoxy-8,9-dichloro-2-benzothiepin-1-yl)methoxy]ethyl4-nitrobenzenesulfonate

9.2-[(1,3,4,5-tetrahydro-7-methoxy-8-trifluoromethyl)-2-benzothiepin-1-yl)methoxy]ethyl4-bromobenzenesulfonate

10.2-[(1,3,4,5-tetrahydro-7,8-methylenedioxy-2-benzothiepin-1-yl)methoxy]ethyl4-nitrobenzenesulfonate

11.2-[(1,3,4,5-tetrahydro-7-methoxy-5-methyl-2-benzothiepin-1-yl)methoxy]ethyl2-methylbenzenesulfonate

12.2-[(1,3,4,5-tetrahydro-7,9-dimethoxy-4,5-dimethoxy-2-benzothiepin-1-yl)methoxy]ethyl 4-nitrobenzenesulfonate

13.2-[(1,3,4,5-tetrahydro-7,8,9-trimethoxy-4-methyl-2-benzothiepin-1-yl)methoxy]ethyl4-nitrobenzenesulfonate

14.2-[(1,3,4,5-tetrahydro-9-methoxy-4-phenyl-2-benzothiepin-1-yl)methoxy]ethyl3-trifluoromethylbenzenesulfonate

15.2-[(1,3,4,5-tetrahydro-7-hydroxy-5-bromo-2-benzothiepin-1-yl)methoxy]ethyl4nitrobenzene sulfonate

16.2-[(1,3,4,5-tetrahydro-7,8-dimethoxy-5,5-dimethyl-2-benzothiepin-1-yl)methoxy]ethyl4-nitrobenzenesulfonate

17.2-[(1,3,4,5-tetrahydro-7,8-dimethoxy-4,4-dimethyl-2-benzothiepin-1-yl)methoxy]ethyl3-trifluoromethylbenzenesulfonate

18.2-[[1,5-dihydro-7,8-dimethoxyspiro[2-benzothiepin-4-(3H)-1'-cyclopentane]-1-yl]methoxy]ethyl4-nitrobenzenesulfonate

19.2-[(8,9-dipropoxy-2,3,3a,4,6,10b-hexahydro-1H-benzo[c]cyclopent[e]thiepin-6-yl)methoxy]ethyl 2-ethylbenzenesulfonate

20.2-[(1,3,4,5-tetrahydro-4-cyclopentyl-8,9-dimethoxy-2-benzothiepen-1-yl)methoxy]ethyl4-nitrobenzenesulfonate

21.2-[(1,3,4,5-tetrahydro-7,8-dihydroxy-5-n-propyl-2-benzothiepin-1-yl)methoxy]ethyl4-nitrobenzenesulfonate

22.2-[(1,3,4,5-tetrahydro-7,8-dimethoxy-9-trifluoromethyl-2-benzothiepin-1-yl)methoxy]ethyl 3-nitrobenzenesulfonate

Similarly, following the procedure of Preparation 7A, from thecorresponding 2-[(1,3,4,5-tetrahydro-2-benzothiepin-1-yl)ethoxy] andpropoxy]ethanols, the corresponding benzenesulfonates can be prepared.

Preparation 8 2-[(1-methyl-7,8-dimethoxyisochroman-1-yl)methoxy]ethanoland derivatives

Ethyl pyruvate (1.00 g, 0.0086 m), 3,4-dimethoxyphenylethanol (1.57 g,0.0086 m), and, 1 ml of BF₃ etherate are stirred at 25° C. in 20 ml ofnitromethane for 45 minutes. The mixture is dissolved in methylenechloride and extracted with aqueous sodium bicarbonate. The organicphase is dried (sodium sulfate), concentrated, and chromatographed onsilica gel to give 1.4 g of6,7-dimethoxy-1-methyl-1-carboethoxyisochroman. A 0.5 g sample of thisis dissolved in ether and treated with 100 mg of LAH. After 10 minutes,the mixture is quenching with ethyl acetate and partitioned between 1 Naqueous sodium hydroxide and CH₂ Cl₂. The organic phase yields 0.34 g of6,7-dimethoxy-1-methyl-1-hydroxymethylisochroman. This is dissolved inTHF and treated sequentially with sodium hydride and theno-tetrahydropyranyl chloroethanol. The adduct, upon treatment with acidand water, yields2-[(7,8-dimethoxy-1-methyl-isochroman-1-yl)methoxy]ethanol. In themanner of Preparation 7, this can be converted to its benzenesulfonates##STR22## Furthermore, 2-[(1-methylisochroman-1-yl)methoxy]ethanols,with various substituents on the isochroman ring, can be prepared byusing the appropriate phenyl ethanols whose substituents, R₁ -R₅ (videsupra), are analogous to those substituents of the isochromans of Table3.

From these compounds, the corresponding substituted benzenesulfonatescan be prepared.

Furthermore, by reacting appropriate phenyl ethanols with varioussubstituted 2-keto esters, the R₈ substituents of the isochroman ring(vide supra) can be varied and the disclosed R₈ substituents can thus beincorporated in the ring system.

Furthermore, various 1-hydroxymethylisochromans can be first treatedwith tetrahydropyranyl chloroethoxyethanol and then with acid and waterto yield the corresponding 2-[2-((isochroman-1-yl)methoxy)ethoxy]ethanol.

Preparation 8A2-[(7,8-dimethyl-3,4-dyhydro-1H-2-benzothiopyran-1-yl)methoxy]ethanol

Ethyl pyruvate, 3,4-dimethoxyphenyl ethanethiol, and BF₃ etherate arestirred in nitromethane. The mixture is partitioned with methylenechloride and aqueous sodium bicarbonate. The organic phase is dried oversodium sulfate, concentrated, and chromatographed. The resultantbenzothiopyran is dissolved in ether and treated with lithium aluminumhydride. The mixture is partitioned between aqueous sodium hydroxide andmethylene chloride. The organic phase yields the corresponding alcohol.This can be dissolved in THF and treated sequentially with sodiumhydroxide and then O-tetrahydropyranyl ether of chloroethanol. Theadduct upon treatment with acid and water, yields2-[(7,8-dimethoxy-3,4-dihydro-1H-2-benzothiopyran-1-yl)methoxy]ethanol.In the manner of example 7A, this can be converted to itsp-nitrobenzenesulfonate.

Furthermore, 2-[(3,4-dihydro-1H-2-benzothiopyran-1-yl)methoxy]ethanolswith various substituents on the thiopyran ring can be prepared by usingthe appropriate phenyl ethanols whose substituents, R₁ -R₅ (vide supra),are analogous to those substituents of the thiopyrans of Table 2A. Thesealcohols can then be converted to their corresponding benzenesulfonatesfollowing the procedure of Preparation 7A and the benzenesulfonylchlorides used to prepare compounds of Table 7A.

Examples 1 through 19 Benzoxepins and benzothiepins

A 1-bromomethylbenzoxepin prepared as in Preparation 1 is stirred inethylene glycol with 1.0 to 2.0 equivalents of HNR₉ R₁₀. An excess oftriethylamine is added. After the reaction is complete, the mixture ispartitioned between aqueous K₂ CO₃ or Na₂ CO₃ and CH₂ Cl₂. The organicphase is dried over Na₂ SO₄ and concentrated. The residue ischromatographed on silica gel. The product is either crystallized orconverted to its salt. The salt is formed by treating a solution of thecompound with an appropriate acid in a suitable solvent.

1-(4-fluorophenyl)-4-[(1,3,4,5-tetrahydro-7,8-dimethoxy-2-benzoxepin-1-yl)methyl]-piperazine

A mixture of 3.50 g (0.0116 moles) of1-bromomethyl-7,8-dimethoxy-2-benzoxepin, 2.51 g (0.0139 moles) ofp-fluorophenyl piperazine, 1.94 ml (0.0139 moles) of triethyl amine, and125 ml of ethylene glycol is heated under N₂ at 100° for 8 hours. Aftercooling, the reaction mixture is extracted with CH₂ Cl₂, aq. NaHCO₃, andH₂ O. The organic layer is filtered through Na₂ SO₄ and taken todryness. The crude reaction mixture is then chromatographed on silicagel using 50% Skellysolve® B as eluant to give 0.60 g (13%) of productwhich is then crystallized from methylenechloride/Skellysolve® B toyield1-(4-fluorophenyl)-4-[(1,3,4,5-tetrahydro-7,8-dimethoxy-2-benzoxepin-1-yl)methyl]-piperazine,m.p. 135°-136° C.

Analysis Calcd. for: C₂₃ H₂₉ FN₂ O₃ C, 68.97; H, 7.30; N, 7.00. Found:C, 68.68; H, 7.12; N, 6.82.

The following 1-methyl substituted-1,3,4,5-tetrahydro-2-benzoxepines areprepared according to the procedure of Example 1, in some cases withminor variations therefrom. The nmr spectra are consistent with theassigned structures.

    __________________________________________________________________________     ##STR23##                                                                    Ex.                                                                              HNR.sub.9 R.sub.10                                                                           (C.°/Hrs)                                                                   Miscellaneous                                                                           M.P. Anal. (found)                                                                            Name                         __________________________________________________________________________        ##STR24##     100/6          135-136                                                                            C=68.68; H=7.12; N=6.82                                                                  1-(4-fluorophenyl)-4-                                                         [1,3,4,5-tetrahydro-7,8-                                                      imethoxy-2-benzoxepin-                                                        1-yl)methyl]-piperazine          ##STR25##     90/1.5         162-166.sup.b                                                                      N=6.05; C=62.86; H=7.30                                                                  1-(2-methoxyphenyl)-4-                                                        [(1,3,4,5-tetrahydro-7,8-                                                      dimethoxy-2-benzoxepin-1                                                     - yl)methyl]-piperazine                                                       monohydrochloride hemi-                                                       hydrate                          ##STR26##     85/1.5; and 20/18                                                                  1. No solvent  used. 2. Excess HNR.sub.9 R.sub. 10                            sed as base.                                                                             75-85.sup.c                                                                       C=60.73; H=7.17; N=3.66                                                                  N-[2-(3,4-dimethoxy-                                                          phenyl)ethyl]-1,3,4,5-                                                        tetrahydro-7,8-dimethoxy-                                                      2-benzoxepin-1-yl-methan                                                     - amine                                                                       monohydrochloride                                                             monohydrate                      ##STR27##     100/7.5                                                                            1. DMF used as solvent. 2. Diisopropyl- ethyl-amine                            used as base.                                                                          196-199.sup.b                                                                      C=61.42; H=7.01; N=9.69                                                                  1-(2-pyridinyl)-4-                                                            [(1,3,4,5-tetrahydro-                                                         7,8-dimethoxy-2-benzoxe-                                                      in-1-yl)methyl-]-pipera-                                                      ine monochloride hemi-                                                        hydrate                          ##STR28##     105/2;                                                                             1. Ethylene glycol monoethylether                                                            C=61.85; H=7.32; N=5.98                                                                  1-(4-methoxyphenyl)-4-                                                        [(1,3,4,5-tetrahydro-7,8-                                                      dimethoxy-2-benzoxepin-1                                                     - yl)methyl]-piperazine                                                       monohydrochloride mono-                                                       hydrochloride                                                                 monohydrate                      ##STR29##     1. Reflux 20 2. 100/4;  20/16                                                      1. THF used as solvent for first 20 hrs.;  then                               replaced with ethylene glycol                                                           172-173.sup.d                                                                      C=55.61; H=5.60; N=2.47                                                                  1-[(1,3,4,5-tetrahydro-                                                       7,8-dimethoxy-2-benzoxe-                                                      in-1-yl)methyl]-4-[3-                                                         (trifluoromethyl)phenyl]-                                                      4-piperidinol                                                                monohydro- bromide               ##STR30##     95/5.5                                                                             1. DMF used as solvent. 2. Diisopropylethyl- amine                            used as base.                                                                           106-108                                                                            C=71.81; H=8.17; N=7.19                                                                  1-phenyl-4-[(1,3,4,5-                                                         tetrahydro-7,8-dimethoxy-                                                      2-benzoxepin-1-yl)-                                                          methyl]-piperazine           8. HN N                1. Toluene used                                                                         139-142.sup.a   1-(2-methylphenyl)-4-                               as solvent.               [(1,3,4,5-tetrahydro-7,8-                           2. Excess amine           dimethoxy-2-benzoxepin-1-                           used as base.             yl)methyl]piperazine         9. HN                                 C=62.68; H=7.25                                                                          1,2,3,4-tetrahydro-6,7-                                            N=3.00     dimethoxy-2-[ (1,3,4,5-                                                       tetrahydro-7,8-dimethoxy-                                                     2-benzoxepin-1-yl)methyl]                                                     --      isoquinoline                                                          monohydro-                                                                    chloride                     __________________________________________________________________________                                                     hemihydrate              

Example 10A1-[2-[(1,3,4,5-tetrahydro-7,8-dimethoxy-2-benzoxepin-1-yl)]ethyl]-4-(3-chlorophenyl)piperazine

A mixture of 2.00 g (7.39 mmol) of2-[(1,3,4,5-tetrahydro-7,8-dimethoxy-2-benzoxepin-1-yl)]ethyl chlorideand 2.8 g (14.5 mmol) of 1-(3-chlorophenyl)piperazine is stirred at 85°for 36 hours in 1 ml of ethylene glycol and 10 ml of toluene. Excesstoluene is added and the solids are removed by filtration from the warmsolution. The organic phase is concentrated. The product wasrecrystallized from CH₂ Cl₂ and toluene to give 1.09 g of product, m.p.125°-126°.

Analysis Calcd. for: C₂₄ H₃₁ ClN₂ O₃ C, 66.88; H, 7.25; N, 6.50. Found:C, 66.68; H, 7.49; N, 6.31.

The following 1-ethyl substituted -1,3,4,5-tetrahydro-2-benzoxepins areprepared according to the procedure of Example 10a, in some cases withminor variations therefrom. The nmr spectra are consistent with theassigned structures. T2 -? - ##STR31##

EXAMPLE 11

Following the procedure used in Examples 1 through 10, but substitutingthe appropriate 1 haloalkylbenzoxepin, the following compounds offormula I can be made (Table 8).

                                      TABLE 8                                     __________________________________________________________________________     ##STR32##                                                                    R.sub.1 '                                                                          R.sub.1 "                                                                          R.sub.1 '"                                                                         R.sub.1 ""                                                                         R.sub.2                                                                            R.sub.3                                                                           R.sub.4                                                                          R.sub.5                                                                           R.sub.6                                                                          R.sub.7                                                                          R.sub.8                                                                             n  NR.sub.9 R.sub.10          __________________________________________________________________________    H    H    propyl                                                                             OCH.sub.3                                                                          H    H   H  H   H  H  H     1                                                                                ##STR33##                  H    H    H    OCH.sub.3                                                                          H    H   H  H   H  H  H     1                                                                                ##STR34##                  OCH.sub.3                                                                          OCH.sub.3                                                                          H    H    H    H   H  H   H  H  H     1                                                                                ##STR35##                  H    OH   H    H    H    Br  H  H   H  H  H     4                                                                                ##STR36##                  H    OCH.sub.3                                                                          OCH.sub.3                                                                          H    CH.sub.3                                                                           CH.sub.3                                                                          H  H   H  H  H     5                                                                                ##STR37##                  H    OCH.sub.3                                                                          OCH.sub.3                                                                          H    H    H   CH.sub.3                                                                         CH.sub.3                                                                          H  H  H     5                                                                                ##STR38##                  H    OCH.sub.3                                                                          OCH.sub.3                                                                          H    H    H                                                                                  ##STR39##                                                                           H  H  H     5                                                                                ##STR40##                  H    OC.sub.3 H.sub.7                                                                   OC.sub.3 H.sub.7                                                                   H    *    H   *  H   H  H  H     5                                                                                ##STR41##                  H    H    OCH.sub.3                                                                          OCH.sub.3                                                                          H    H                                                                                  ##STR42##                                                                       H   H  H  H     2                                                                                ##STR43##                  H    OH   OH   H    C.sub.3 H.sub.7                                                                    H   H  H   H  H  H     2                                                                                ##STR44##                  H    OCH.sub.3                                                                          OCH.sub.3                                                                          CF.sub.3                                                                           H    H   H  H   H  H  H     1                                                                                ##STR45##                  H    OCH.sub.3                                                                          OCH.sub.3                                                                          H    H    H   H  H   H  H  H     2                                                                                ##STR46##                  H    OCH.sub.3                                                                          OCH.sub.3                                                                          H    H    H   H  H   H  H  H     2                                                                                ##STR47##                  H    OCH.sub.3                                                                          OCH.sub.3                                                                          H    CH.sub.3                                                                           CH.sub.3                                                                          H  H   H  H  H     2                                                                                ##STR48##                  H    OC.sub.2 H.sub.5                                                                   H    H    H    H   H  H   H  H  H     1                                                                                ##STR49##                  H    OCH.sub.3                                                                          OCH.sub.3                                                                          OCH.sub.3                                                                          H    H   H  H   H  H  H     1                                                                                ##STR50##                  OCH.sub.3                                                                          OH   H    H    H    H   H  H   H  H  H     1                                                                                ##STR51##                  H    OCH.sub.3                                                                          Br   H    H    H   H  H   H  H  H     1                                                                                ##STR52##                  H    OCH.sub.3                                                                          Cl   Cl   H    H   H  H   H  H  H     1                                                                                ##STR53##                  H    OCH.sub.3                                                                          CF.sub.3                                                                           H    H    H   H  H   H  H  H     2                                                                                ##STR54##                        ##STR55##                                                                              H    H    H   H  H   H  H  H     3                                                                                ##STR56##                  H    OCH.sub.3                                                                          H    H    CH.sub.3                                                                           H   H  H   H  H  H     3                                                                                ##STR57##                  H    OCH.sub.3                                                                          H    OCH.sub.3                                                                          CH.sub.3                                                                           H   CH.sub.3                                                                         H   H  H  H     3                                                                                ##STR58##                  H    OCH.sub.3                                                                          OCH.sub.3                                                                          OCH.sub.3                                                                          H    H   H  CH.sub.3                                                                          H  H  H     4                                                                                ##STR59##                  H    H    H    OCH.sub.3                                                                          H    H   H                                                                                 ##STR60##                                                                        H  H  H     4                                                                                ##STR61##                  H    OCH.sub.3                                                                          OCH.sub.3                                                                          H    H    H   CH.sub. 3CH.sub.3                                                                    H  H  H     2                                                                                ##STR62##                  H    OCH.sub.3                                                                          OCH.sub.3                                                                          H    H    H   H  H   CH.sub.3                                                                         CH.sub.3                                                                         H     2                                                                                ##STR63##                  H    OCH.sub.3                                                                          OCH.sub. 3                                                                         H    CH.sub.3                                                                           CH.sub.3                                                                          H  H   H  H  H     2                                                                                ##STR64##                  H    OCH.sub.3                                                                          OCH.sub.3                                                                          H    H    H   CH.sub.3                                                                         CH.sub.3                                                                          H  H  H     2                                                                                ##STR65##                  H                                                                                   ##STR66##                                                                              H         H   H  H   CH.sub.3                                                                         CH.sub.3                                                                         H     2                                                                                ##STR67##                  H    OCH.sub.3                                                                          OCH.sub.3                                                                          H    CH.sub.3                                                                           CH.sub.3                                                                          H  H   H  H  H     2                                                                                ##STR68##                  H    OCH.sub.3                                                                          OCH.sub.3                                                                          H    H    H   CH.sub.3                                                                         CH.sub.3                                                                          H  H  H     2                                                                                ##STR69##                  H    OCH.sub.3                                                                          OCH.sub.3                                                                          H    H    H   H  H   CH.sub.3                                                                         CH.sub.3                                                                         H     2                                                                                ##STR70##                  H    OCH.sub.3                                                                          OCH.sub.3                                                                          H    CH.sub.3                                                                           CH.sub.3                                                                          H  H   H  H  H     2                                                                                ##STR71##                  H    OCH.sub.3                                                                          OCH.sub.3                                                                          H    CH.sub.3                                                                           CH.sub.3                                                                          H  H   H  H  H     2                                                                                ##STR72##                  H    OCH.sub.3                                                                          OCH.sub.3                                                                          H    H    H   H  H   CH.sub.3                                                                         CH.sub.3                                                                         H     2                                                                                ##STR73##                  H    OCH.sub. 3                                                                         OCH.sub.3                                                                          H    CH.sub.3                                                                           CH.sub.3                                                                          H  H   H  H  H     2                                                                                ##STR74##                  H    OCH.sub.3                                                                          OCH.sub.3                                                                          H    H    H   CH.sub.3                                                                         CH.sub.3                                                                          H  H  CH.sub.3                                                                            2                                                                                ##STR75##                  H    OCH.sub.3                                                                          OCH.sub.3                                                                          H    H    H   H  H   H  H  CH.sub.3                                                                            2                                                                                ##STR76##                  H    OCH.sub.3                                                                          OCH.sub.3                                                                          H    H    H   H  H   H  H  CH.sub.3                                                                            2                                                                                ##STR77##                  H    OCH.sub.3                                                                          OCH.sub.3                                                                          H    CH.sub.3                                                                           CH.sub.3                                                                          H  H   H  H  CH.sub.3                                                                            2                                                                                ##STR78##                  H    OCH.sub.3                                                                          OCH.sub.3                                                                          H    H    H   CH.sub.3                                                                         CH.sub.3                                                                          H  H  CH.sub.3                                                                            2                                                                                ##STR79##                  H    OCH.sub.3                                                                          OCH.sub.3                                                                          H    H    H   H  H   CH.sub.3                                                                         CH.sub.3                                                                         CH.sub.3                                                                            2                                                                                ##STR80##                  H    OCH.sub.3                                                                          OCH.sub.3                                                                          H    CH.sub.3                                                                           CH.sub.3                                                                          H  H   H  H  CH.sub.3                                                                            2                                                                                ##STR81##                  H    OCH.sub.3                                                                          OCH.sub.3                                                                          H    H    H   CH.sub.3                                                                         CH.sub.3                                                                          H  H  CH.sub.3                                                                            2                                                                                ##STR82##                  H    OCH.sub.3                                                                          OCH.sub.3                                                                          H    H    H   H  H   CH.sub.3                                                                         CH.sub.3                                                                         CH.sub.3                                                                            2                                                                                ##STR83##                  H    OCH.sub.3                                                                          OCH.sub.3                                                                          H    H    H   CH.sub.3                                                                         CH.sub.3                                                                          H  H  CH.sub.3                                                                            3                                                                                ##STR84##                  H    OCH.sub.3                                                                          OCH.sub.3                                                                          H    H    H   H  H   H  H  CH.sub.3                                                                            4                                                                                ##STR85##                  H    OCH.sub.3                                                                          OCH.sub.3                                                                          H    CH.sub.3                                                                           CH.sub.3                                                                          H  H   H  H  CH.sub.3                                                                            2                                                                                ##STR86##                  H    OCH.sub.3                                                                          OCH.sub.3                                                                          H    H    H   CH.sub.3                                                                         CH.sub.3                                                                          H  H  CH.sub.3                                                                            2                                                                                ##STR87##                  H    OCH.sub.3                                                                          OCH.sub.3                                                                          H    H    H   H  H   CH.sub.3                                                                         CH.sub.3                                                                         CH.sub.3                                                                            2                                                                                ##STR88##                  H                                                                                   ##STR89##                                                                              H    CH.sub.3                                                                           CH.sub.3                                                                          H  H   H  H                                                                                 ##STR90##                                                                          2                                                                                ##STR91##                  H    OCH.sub.3                                                                          OCH.sub.3                                                                          H    H    H   CH.sub.3                                                                         CH.sub.3                                                                          H  H                                                                                 ##STR92##                                                                          2                                                                                ##STR93##                  H    OCH.sub.3                                                                          OCH.sub.3                                                                          H    H    H   H  H   CH.sub.3                                                                         CH.sub.3                                                                          ##STR94##                                                                          2                                                                                ##STR95##                  H    OCH.sub.3                                                                          OCH.sub.3                                                                          H    CH.sub.3                                                                           CH.sub.3                                                                          H  H   H  H                                                                                 ##STR96##                                                                          2                                                                                ##STR97##                  H    OCH.sub.3                                                                          OCH.sub.3                                                                          H    H    H   CH.sub.3                                                                         CH.sub.3                                                                          H  H                                                                                 ##STR98##                                                                          2                                                                                ##STR99##                  H    OCH.sub.3                                                                          OCH.sub.3                                                                          H    H    H   Cl H   CH.sub.3                                                                         CH.sub.3                                                                          ##STR100##                                                                         2                                                                                ##STR101##                 H    OCH.sub.3                                                                          OCH.sub.3                                                                          H    CH.sub.3                                                                           CH.sub.3                                                                          H  H   H  H                                                                                 ##STR102##                                                                         2                                                                                ##STR103##                 H    OCH.sub.3                                                                          OCH.sub. 3                                                                         H    H    H   CH.sub.3                                                                         CH.sub.3                                                                          H  H                                                                                 ##STR104##                                                                         2                                                                                ##STR105##                 H    OCH.sub.3                                                                          OCH.sub.3                                                                          H    H    H   H  H   CH.sub.3                                                                         CH.sub.3                                                                          ##STR106##                                                                         2                                                                                ##STR107##                 H    OCH.sub.3                                                                          OCH.sub.3                                                                          H    CH.sub.3                                                                           CH.sub.3                                                                          H  H   H  H                                                                                 ##STR108##                                                                         2                                                                                ##STR109##                 H    OCH.sub.3                                                                          OCH.sub.3                                                                          H    CH.sub.3                                                                           CH.sub.3                                                                          H  H   H  H                                                                                 ##STR110##                                                                         2                                                                                ##STR111##                 H    OCH.sub.3                                                                          OCH.sub.3                                                                          H    H    H   C.sub.3 H.sub.7                                                                  H   CH.sub.3                                                                         CH.sub.3                                                                          ##STR112##                                                                            ##STR113##                 H    OCH.sub.3                                                                          OCH.sub.3                                                                          H    CH.sub.3                                                                           CH.sub.3                                                                          H  H   H  H  CH.sub.3                                                                            3                                                                                ##STR114##                 H    H    H    OCH.sub.3                                                                          C.sub.2 H.sub.5                                                                    C.sub.2 H.sub.5                                                                   H  H   H  H  H     3                                                                                ##STR115##                 H    OCH.sub.3                                                                          OCH.sub.3                                                                          H    C.sub.3 H.sub.7                                                                    C.sub.3 H.sub.7                                                                   H  H   H  H  H     3                                                                                ##STR116##                 H    OC.sub.2 H.sub.5                                                                   H    H    CH.sub.3                                                                           CH.sub.3                                                                          H  H   H  H  CH.sub.3                                                                            3                                                                                ##STR117##                 H    OCH.sub.3                                                                          OCH.sub.3                                                                          H    nC.sub.4 H.sub.9                                                                   nC.sub.4 H.sub.9                                                                  H  H   H  H  H     2                                                                                ##STR118##                 OH   H    H    H    C.sub.2 H.sub.5                                                                    C.sub.3 H.sub.7                                                                   H  H   H  H  H     3                                                                                ##STR119##                 H    OCH.sub.3                                                                          OCH.sub.3                                                                          H    H    H   H  H   H  H  H     2                                                                                ##STR120##                 H    OCH.sub.3                                                                          OCH.sub.3                                                                          H    Cl   H   H  H   H  H  H     1                                                                                ##STR121##                 H    OCH.sub.3                                                                          CF.sub.3                                                                           H    H    H   H  H   H  H  CH.sub.3                                                                            3                                                                                ##STR122##                 H                                                                                   ##STR123##                                                                             H                                                                                   ##STR124##                                                                        H   H  H   H  H  H     1                                                                                ##STR125##                 H    OCH.sub.3                                                                          OCH.sub.3                                                                          H    CH.sub.3                                                                           H   H  H   H  H  H     1                                                                                ##STR126##                 H    OCH.sub.3                                                                          H    H                                                                                   ##STR127##                                                                        H   H  H   H  H  CH.sub.3                                                                            2                                                                                ##STR128##                 H    OCH.sub.3                                                                          H    H    OCH.sub.3                                                                          H   H  H   H  H  H     2                                                                                ##STR129##                 H    OCH.sub.3                                                                          OCH.sub.3                                                                          H    Br   H   H  CH.sub.3                                                                          CH.sub.3                                                                         H  H     2                                                                                ##STR130##                 H    OC.sub.2 H.sub.5                                                                   H    H    Cl   H   CH.sub.3                                                                         H   H  H  H     2                                                                                ##STR131##                 H    OCH.sub.3                                                                          OCH.sub.3                                                                          OCH.sub.3                                                                          H    CH.sub.3                                                                           ##STR132##                                                                          H  H  H     2                                                                                ##STR133##                 H    OCH.sub.3                                                                          H    H    CH.sub.3                                                                           Cl  H  H   H  H  H     3                                                                                ##STR134##                 H    OCH.sub.3                                                                          H    H    Cl   H   H  H   H  H  H     3                                                                                ##STR135##                 H    OCH.sub.3                                                                          Cl   H    H    H   H  H   H  H  CH.sub.3                                                                            2                                                                                ##STR136##                 H    OCH.sub.3                                                                          OCH.sub.3                                                                          H    CH.sub.3                                                                           CH.sub.3                                                                          H  H   H  H  H     2                                                                                ##STR137##                 H    H    OCH.sub.3                                                                          H    CH.sub.3                                                                           H   CH.sub.3                                                                         H   H  H  CH.sub.3                                                                            5                                                                                ##STR138##                 H    CH.sub.3                                                                           H    H    OCH.sub.3                                                                          H   H  H   H  H  CH.sub.3                                                                            5                                                                                ##STR139##                 H    H    H    OCH.sub.3                                                                          H    H   H                                                                                 ##STR140##                                                                       H  H  CH.sub.3                                                                            3                                                                                ##STR141##                 H    OCH.sub.3                                                                          H    H    H    H   H  H   H  H  H     3                                                                                ##STR142##                 H    OCH.sub.3                                                                          OCH.sub.3                                                                          H    CH.sub.3                                                                           CH.sub.3                                                                          H  H   H  H  H     4                                                                                ##STR143##                 __________________________________________________________________________     ##STR144##                                                               

EXAMPLE 12

Following the procedure used in Examples 1 through 11, but substitutinghalo branched chain benzoxepins for the corresponding1-haloalkylbenzoxepins the following compounds can be made.

    TABLE 9      ##STR145##                 Branch  R.sub.1 ' R.sub.1 " R.sub.1 '" R.sub.1 "" R.sub.2     R.sub.3 R.sub.4 R.sub.5 R.sub.6 R.sub.7 R.sub.8 Chain NR.sub.9      R.sub.10                 H H C.sub.3 H.sub.7 OCH.sub.3 H H H H H H H      ##STR146##      ##STR147##      H H H OCH.sub.3 H H H H H H H      ##STR148##      ##STR149##      OCH.sub.3 OCH.sub.3 H H H H H H H H H      ##STR150##      ##STR151##      H OC.sub.2      H.sub.5 H H H H H H H H H     ##STR152##      ##STR153##      H OCH.sub.3 OCH.sub.3 OCH.sub.3 H H H H H H H      ##STR154##      ##STR155##      H OH OCH.sub.3 H H H H H H H H      ##STR156##      ##STR157##      H OCH.sub.3 Br H H H CH.sub.3 H H H H      ##STR158##      ##STR159##      H OCH.sub.3 Cl Cl H H H H H H H      ##STR160##      ##STR161##      H OCH.sub.3 CF.sub.3 H H H H H H H H      ##STR162##      ##STR163##                  H      ##STR164##      H H H H H H H H      ##STR165##      ##STR166##                   H OCH.sub.3 H H CH.sub.3 H H H H H H      ##STR167##      ##STR168##      H OCH.sub.3 H OCH.sub.3 CH.sub.3 H CH.sub.3 H H H H      ##STR169##      ##STR170##      H OCH.sub.3 OCH.sub.3 OCH.sub.3 H H H CH.sub.3 H H H      ##STR171##      ##STR172##      H H H OCH.sub.3 H H H      ##STR173##      H H H      ##STR174##      ##STR175##      H OH H H H Br H H H H H      ##STR176##      ##STR177##      H OCH.sub.3 OCH.sub.3 H CH.sub.3 CH.sub.3 H H H H CH.sub.3      ##STR178##      ##STR179##      H OCH.sub.3 OCH.sub.3 H H H CH.sub.3 CH.sub.3 H H CH.sub.3      ##STR180##      ##STR181##       H OCH.sub.3 OCH.sub.3 H H H      ##STR182##       H H CH.sub.3      ##STR183##      ##STR184##      H OC.sub.3 H.sub.7 OC.sub.3      H.sub.7 H H H H H H H     ##STR185##      ##STR186##      ##STR187##

EXAMPLE 131-[2-[(1,3,4,5-tetrahydro-7,8-dimethoxy-2-benzoxepin-1-yl)methoxy]ethyl]-4-(2-methoxyphenyl)piperazine

A mixture of 0.50 g (1.07 mmoles) of[2-[(1,3,4,5-tetrahydro-7,8-dimethoxy-2-benzoxepin-1-yl)methoxy]ethyl]-4-nitrobenzenesulfonate,0.22 g (1.07 mmoles) of o-methoxyphenylpiperazine, 0.15 ml (1.07 mmoles)of triethylamine, and 20 ml of tetrahydrofuran is stirred at roomtemperature for 24 hours. After removing the tetrahydrofuran in vacuo,the reaction mixture is extracted with methylene chloride and aqueoussodium bicarbonate. The organic layer is filtered through sodiumsulfate, taken to dryness, and chromatographed on silica gel using 3%methanol:methylene chloride eluent to give 0.40 g (82%) of1-[2-[(1,3,4,5-tetrahydro-7,8-dimethoxy-2-benzoxepin-1-yl)methoxy]ethyl]-4-(2-methoxyphenyl)piperazine.The dihydrochloride salt was prepared with hydrochloric acid in ethylether, m.p. 172°-175°.

Analysis: Calc'd. for C₂₆ H₃₆ N₂ O₅.2HCl.H₂ O C, 57.03; H, 7.36; N,5.12; Cl, 12.95. Found: C, 56.94; H, 7.29; N, 5.48; Cl, 12.98.

EXAMPLE 141-[2-[(1,3,4,5-tetrahydro-7,8-dimethoxy-2-benzoxepin-1-yl)methoxy]ethyl]-4-hydroxy-4-(3-trifluoromethylphenyl)piperidine

A mixture of 0.10 g (1.50 mmoles) of2-[(1,3,4,5-tetrahydro-7,8-dimethoxy-2-benzoxepine-1-yl)methoxy]ethyl4-nitrobenzenesulfonate, 0.37 g (1.50 mmoles) of4-hydroxy-4-(3-trifluoromethylphenyl)piperidine, 0.21 ml (1.50 mmoles)of triethylamine and 30 ml of tetrahydrofuran is stirred at roomtemperature for 3 days, at 50° for 1 day, and again at room temperaturefor 2 days, after which the tetrahydrofuran is removed in vacuo.

The reaction mixture is extracted with methylene chloride and aqueoussodium bicarbonate. The organic layer is filtered through sodium sulfateand taken to dryness and chromatographed on silica gel with 2%methanol:0.5% ammonium hydroxide:methylene chloride as eluent to give0.46 g (60%) of the titled product. The hydrochloride salt is preparedwith hydrochloric acid/ethyl ether, m.p. 156°-159°.

Analysis: Calc'd. for C₂₇ H₃₄ F₃ NO₅.HCl.1/2H₂ O C, 58.43; H, 6.54; N,2.52; Cl, 6.34. Found: C, 58.60; H, 6.49; N, 2.85; Cl, 7.08.

EXAMPLE 151-[2-[(1,3,4,5-tetrahydro-7,8-dimethoxy-2-benzoxepin-1-yl)methoxy]ethyl]-4-(4-fluorophenyl)-piperazine

A mixture of 400 mg of2-[(1,3,4,5-tetrahydro-7,8-dimethoxy-2-benzoxepin-1-yl)methoxy]ethyl-4-nitrobenzenesulfonate,150 mg of 4-fluorophenylpiperazine, 0.12 ml of triethylamine andtetrahydrofuran as solvent is stirred at room temperature for 18 hoursafter which the tetrahydrofuran is removed in vacuo. The reactionmixture is extracted with methylene chloride and aqueous sodiumbicarbonate. The organic layer is filtered through sodium sulfate andtaken to dryness. The residue is purified by chromatography. The productis crystallized from methylene chloride and Skelly B, and ether, m.p.114°-114.5°.

EXAMPLE 161-[2-[(1,3,4,5-tetrahydro-7,8-dimethoxy-2-benzoxepin-1-yl)methoxy]ethyl]-4-(4-fluorophenyl)piperazine

A mixture of 1.27 g (4.42 mmoles) of2-[(1,3,4,5-tetrahydro-7,8-dimethoxy-2-benzoxepin-1-yl)methoxy]ethylchloride, and 1.52 g (8.44 mmoles) of 1-fluorophenyl piperazine isstirred for 60 hours at 90°. neat. The product is isolated andcrystallized as in Example 15.

EXAMPLE 171-[2-[(1,3,4,5-tetrahydro-7,8-dimethoxy-2-benzoxepin-1-yl)methoxy]ethyl]-4-(2-pyridyl)piperazine

A mixture of 1.00 g (3.32 mmoles) of2-[(1,3,4,5-tetrahydro-7,8-dimethoxy-2-benzoxepin-1-yl)methoxy]ethylchloride and 1.14 g (6.65 mmoles) of 95% 2-pyridylpiperazine is stirredat 90° for 20 hours. Approximately 3 ml of toluene is then added and thereaction mixture is heated for an additional 28 hours. After cooling,the reaction mixture is filtered, washing with toluene, and the filtrateis extracted with (1) aqueous sodium bicarbonate and (2) brine. Theorganic layer is taken to dryness and the residue is chromatographed onsilica gel using 3% methanol:0.5% ammonium hydroxide in methylenechloride as eluent to give 1.30 g (92%) of the stated product. Thehydrochloric acid salt (dihydrate) was prepared from hydrogen chloridein ethanol.

Analysis: Calc'd. for C₂₄ H₃₃ N₃ O₄.HCl.2H₂ O C, 57.65; H, 7.46; N,8.40. Found: C, 57.31; H, 7.69; N, 8.23.

EXAMPLE 18

Following the procedure used in Example 12 through 17 but substitutingthe appropriate 1-[2-[(1,3,4,5-tetrahydro-2-benzoxepin-1-yl)alkoxy]alkylchlorides or benzene sulfonates and the appropriate amines, thefollowing compounds can be made.

                                      TABLE 10                                    __________________________________________________________________________     ##STR188##                                                                   R.sub.1 '                                                                          R.sub.1 "                                                                          R.sub.1 '"                                                                         R.sub.1 ""                                                                         R.sub.2                                                                           R.sub.3                                                                           R.sub.4                                                                           R.sub.5                                                                           R.sub.6                                                                          R.sub.7                                                                          R.sub.8                                                                          m q NR.sub.21 R.sub.22           __________________________________________________________________________    H    H    propyl                                                                             OCH.sub.3                                                                          H   H   H   H   H  H  H  1 1                                                                                ##STR189##                  H    H    H    OCH.sub.3                                                                          H   H   H   H   H  H  H  1 2                                                                                ##STR190##                  OCH.sub.3                                                                          OCH.sub.3                                                                          H    H    H   H   H   H   H  H  H  1 3                                                                                ##STR191##                  H    OC.sub.2 H.sub.5                                                                   H    H    H   H   H   H   H  H  H  2 1                                                                                ##STR192##                  H    OCH.sub.3                                                                          OCH.sub.3                                                                          OCH.sub.3                                                                          H   H   H   H   H  H  H  2 2                                                                                ##STR193##                  OCH.sub.3                                                                          OH   H    H    H   H   H   H   H  H  H  2 3                                                                                ##STR194##                  H    OCH.sub.3                                                                          Br   H    H   H   H   H   H  H  H  3 1                                                                                ##STR195##                  H    OCH.sub.3                                                                          Cl   Cl   H   H   H   H   H  H  H  3 2                                                                                ##STR196##                  H    OCH.sub.3                                                                          CF.sub.3                                                                           H    H   H   H   H   H  H  H  3 3                                                                                ##STR197##                        ##STR198##                                                                             H    H   H   H   H   H  H  H  1 1                                                                                ##STR199##                  H    OCH.sub.3                                                                          H    H    CH.sub.3                                                                          H   H   H   H  H  H  2 1                                                                                ##STR200##                  H    OCH.sub.3                                                                          H    OCH.sub.3                                                                          CH.sub.3                                                                          H   CH.sub.3                                                                          H   H  H  H  3 2                                                                                ##STR201##                  H    OCH.sub.3                                                                          OCH.sub.3                                                                          OCH.sub.3                                                                          H   H   OCH.sub.3                                                                         CH.sub.3                                                                          H  H  H  2 3                                                                                ##STR202##                  H    H    H    OCH.sub.3                                                                          H   H   H                                                                                  ##STR203##                                                                       H  H  H  1 3                                                                                ##STR204##                  H    OH   H    H    H   Br  H   H   H  H  H  1 1                                                                                ##STR205##                  H    OCH.sub.3                                                                          OCH.sub.3                                                                          H    CH.sub.3                                                                          CH.sub.3                                                                          H   H   H  H  H  2 2                                                                                ##STR206##                  H    OCH.sub.3                                                                          OCH.sub.3                                                                          H    H   H   CH.sub.3                                                                          CH.sub.3                                                                          H  H  H  3 3                                                                                ##STR207##                  H    OCH.sub.3                                                                          OCH.sub.3                                                                          H                                                                                   ##STR208##                                                                           H   H   H  H  H  3 1                                                                                ##STR209##                  H    OC.sub.3 H.sub.7                                                                   OC.sub.3 H.sub.7                                                                   H    H*  H   *   H   H  H  H  1 1                                                                                ##STR210##                  H    H    OCH.sub.3                                                                          OCH.sub.3                                                                          H   H                                                                                  ##STR211##                                                                       H   H  H  H  1 1                                                                                ##STR212##                  H    OH   OH   H    C.sub.3 H.sub.7                                                                   H   H   H   H  H  H  1 1                                                                                ##STR213##                  H    OCH.sub.3                                                                          OCH.sub.3                                                                          H    H   H   H   H   H  H  CH.sub.3                                                                         1 3 N(CH.sub.3).sub.2            H    OCH.sub.3                                                                          OCH.sub.3                                                                          H    H   H   H   H   H  H  CH.sub.3                                                                         1 4                                                                                ##STR214##                  H    OCH.sub.3                                                                          OCH.sub.3                                                                          H    CH.sub.3                                                                          CH.sub.3                                                                          H   H   H  H  CH.sub.3                                                                         1 4 NH butyl                     H    OCH.sub.3                                                                          OCH.sub.3                                                                          H    H   H   CH.sub.3                                                                          CH.sub.3                                                                          H  H  CH.sub.3                                                                         2 3                                                                                ##STR215##                  H    OCH.sub.3                                                                          OCH.sub.3                                                                          H    CH.sub.3                                                                          CH.sub.3                                                                          H   H   H  H  C.sub.6 H.sub.5                                                                  1 3 NHt-butyl                    H    OCH.sub.3                                                                          OCH.sub.3                                                                          H    H   H   H   H   H  H  C.sub.6 H.sub.5                                                                  1 3 NH.sub.2                     __________________________________________________________________________     ##STR216##                                                               

EXAMPLE 18A

Following procedures similar to those of Examples 1 to 11, butsubstituting the appropriate 1-haloalkyl-2-benzothiepin for1-haloalkyl-2-benzoxepin, benzothiepins of Table II can be prepared.

    TABLE 11      ##STR217##      R.sub.1 ' R.sub.1 " R.sub.1 '" R.sub.1 "" R.sub.2 R.sub.3 R.sub.4     R.sub.5 R.sub.6 R.sub.7 R.sub.8 n NR.sub.9      R.sub.10                                     H H propyl OCH.sub.3 H H H     H H H H 1      ##STR218##      H H H OCH.sub.3 H H H H H H H 1      ##STR219##      OCH.sub.3 OCH.sub.3 H H H H H H H H H 1      ##STR220##      H OH H H H Br H H H H H 4      ##STR221##      H OCH.sub.3 OCH.sub.3 H CH.sub.3 CH.sub.3 H H H H H 5      ##STR222##      H OCH.sub.3 OCH.sub.3 H H H CH.sub.3 CH.sub.3 H H H 5      ##STR223##                  H OCH.sub.3 OCH.sub.3 H H H      ##STR224##      H H H 5      ##STR225##                   H OC.sub.3 H.sub.7 OC.sub.3 H.sub.7 H * H * H H H H 5      ##STR226##      H H OCH.sub.3 OCH.sub.3 H H      ##STR227##      H H H H 2      ##STR228##      H OH OH H C.sub.3      H.sub.7 H H H H H H 2     ##STR229##      H OCH.sub.3 OCH.sub.3 CF.sub.3 H H H H H H H 1      ##STR230##      H OCH.sub.3 OCH.sub.3 H H H H H H H H 2      ##STR231##      H OCH.sub.3 OCH.sub.3 H H H H H H H H 2      ##STR232##      H OCH.sub.3 OCH.sub.3 H CH.sub.3 CH.sub.3 H H H H H 2      ##STR233##      H OC.sub.2      H.sub.5 H H H H H H H H H 1     ##STR234##      H OCH.sub.3 OCH.sub. 3 OCH.sub.3 H H H H H H H 1      ##STR235##      OCH.sub.3 OH H H H H H H H H H 1      ##STR236##      H OCH.sub.3 Br H H H H H H H H 1      ##STR237##      H OCH.sub.3 Cl Cl H H H H H H H 1      ##STR238##      H OCH.sub.3 CF.sub.3 H H H H H H H H 2      ##STR239##                  H      ##STR240##      H H H H H H H H 3      ##STR241##                   H OCH.sub.3 H H CH.sub.3 H H H H H H 3      ##STR242##      H OCH.sub.3 H OCH.sub.3 CH.sub.3 H CH.sub.3 H H H H 3      ##STR243##      H OCH.sub.3 OCH.sub.3 OCH.sub.3 H H H CH.sub.3 H H H 4      ##STR244##      H H H OCH.sub.3 H H H      ##STR245##      H H H 4      ##STR246##      H OCH.sub.3 OCH.sub.3 H H H CH.sub.3 CH.sub.3 H H H 2      ##STR247##      H OCH.sub.3 OCH.sub.3 H H H H H CH.sub.3 CH.sub.3 H 2      ##STR248##      H OCH.sub.3 OCH.sub.3 H CH.sub.3 CH.sub.3 H H H H H 2      ##STR249##      H OCH.sub.3 OCH.sub.3 H H H CH.sub.3 CH.sub.3 H H H 2      ##STR250##                 H      ##STR251##      H H H H CH.sub.3 CH.sub.3 H 2      ##STR252##                   H OCH.sub.3 OCH.sub.3 H CH.sub.3 CH.sub.3 H H H H H 2      ##STR253##      H OCH.sub.3 OCH.sub.3 H H H CH.sub.3 CH.sub.3 H H H 2      ##STR254##      H OCH.sub.3 OCH.sub.3 H H H H H CH.sub.3 CH.sub.3 H 2      ##STR255##      H OCH.sub.3 OCH.sub.3 H CH.sub.3 CH.sub.3 H H H H H 2      ##STR256##      H OCH.sub.3 OCH.sub.3 H CH.sub.3 CH.sub.3 H H H H H 2      ##STR257##      H OCH.sub.3 OCH.sub.3 H H H H H CH.sub.3 CH.sub.3 H 2      ##STR258##      H OCH.sub.3 OCH.sub.3 H CH.sub.3 CH.sub.3 H H H H H 2      ##STR259##      H OCH.sub.3 OCH.sub.3 H H H CH.sub.3 CH.sub.3 H H CH.sub.3 2      ##STR260##      H OCH.sub.3 OCH.sub.3 H H H H H H H CH.sub.3 2      ##STR261##      H OCH.sub.3 OCH.sub.3 H H H H H H H CH.sub.3 2      ##STR262##      H OCH.sub.3 OCH.sub.3 H CH.sub.3 CH.sub.3 H H H H CH.sub.3 2      ##STR263##      H OCH.sub.3 OCH.sub.3 H H H CH.sub.3 CH.sub.3 H H CH.sub.3 2      ##STR264##      H OCH.sub.3 OCH.sub.3 H H H H H CH.sub.3 CH.sub.3 CH.sub.3 2      ##STR265##      H OCH.sub.3 OCH.sub.3 H CH.sub.3 CH.sub.3 H H H H CH.sub. 3 2      ##STR266##      H OCH.sub.3 OCH.sub.3 H H H CH.sub.3 CH.sub.3 H H CH.sub.3 2      ##STR267##      H OCH.sub.3 OCH.sub.3 H H H H H CH.sub.3 CH.sub.3 CH.sub.3 2      ##STR268##      H OCH.sub.3 OCH.sub.3 H H H CH.sub.3 CH.sub.3 H H CH.sub.3 3      ##STR269##      H OCH.sub.3 OCH.sub.3 H H H H H H H CH.sub.3 4      ##STR270##      H OCH.sub.3 OCH.sub.3 H CH.sub.3 CH.sub.3 H H H H CH.sub.3 2      ##STR271##      H OCH.sub.3 OCH.sub.3 H H H CH.sub.3 CH.sub.3 H H CH.sub.3 2      ##STR272##      H OCH.sub.3 OCH.sub.3 H H H H H CH.sub.3 CH.sub.3 CH.sub.3 2      ##STR273##                  H      ##STR274##      H CH.sub.3 CH.sub.3 H H H H      ##STR275##      2      ##STR276##                   H OCH.sub.3 OCH.sub.3 H H H CH.sub. 3 CH.sub.3 H H      ##STR277##      2      ##STR278##      H OCH.sub.3 OCH.sub.3 H H H H H CH.sub.3 CH.sub.3      ##STR279##      2      ##STR280##      H OCH.sub.3 OCH.sub.3 H CH.sub.3 CH.sub.3 H H H H      ##STR281##      2      ##STR282##      H OCH.sub.3 OCH.sub.3 H H H CH.sub.3 CH.sub.3 H H      ##STR283##      2      ##STR284##      H OCH.sub.3 OCH.sub.3 H H H Cl H CH.sub.3 CH.sub.3      ##STR285##      2      ##STR286##      H OCH.sub.3 OCH.sub.3 H CH.sub.3 CH.sub.3 H H H H      ##STR287##      2      ##STR288##      H OCH.sub.3 OCH.sub.3 H H H CH.sub.3 CH.sub.3 H H      ##STR289##      2      ##STR290##      H OCH.sub.3 OCH.sub.3 H H H H H CH.sub.3 CH.sub.3      ##STR291##      2      ##STR292##      H OCH.sub.3 OCH.sub.3 H CH.sub.3 CH.sub.3 H H H H      ##STR293##      2      ##STR294##      H OCH.sub.3 OCH.sub.3 H CH.sub.3 CH.sub.3 H H H H      ##STR295##      2      ##STR296##      H OCH.sub.3 OCH.sub.3 H H H C.sub.3 H.sub.7 H CH.sub.3 CH.sub.3      ##STR297##      ##STR298##      H OCH.sub.3 OCH.sub.3 H CH.sub.3 CH.sub.3 H H H H CH.sub.3 3      ##STR299##      H H H OCH.sub.3 C.sub.2 H.sub.5 C.sub.2      H.sub.5 H H H H H 3     ##STR300##      H OCH.sub.3 OCH.sub.3 H C.sub.3 H.sub.7 C.sub.3 H.sub.7 H H H H H 3      ##STR301##      H OC.sub.2      H.sub.5 H H CH.sub.3 CH.sub.3 H H H H CH.sub.3 3     ##STR302##      H OCH.sub.3 OCH.sub.3 H nC.sub.4 H.sub.9 nC.sub.4 H.sub.9 H H H H H 2      ##STR303##      OH H H H C.sub.2 H.sub.5 C.sub.3      H.sub.7 H H H H H 3     ##STR304##      H OCH.sub.3 OCH.sub.3 H H H H H H H H 2      ##STR305##      H OCH.sub.3 OCH.sub.3 H Cl H H H H H H 1      ##STR306##      H OCH.sub.3 CF.sub.3 H H H H H H H CH.sub.3 3      ##STR307##                  H      ##STR308##      H      ##STR309##      H H H H H H 1      ##STR310##                   H OCH.sub.3 OCH.sub.3 H CH.sub.3 H H H H H H 1      ##STR311##      H OCH.sub.3 H H      ##STR312##      H H H H H CH.sub.3 2      ##STR313##      H OCH.sub.3 H H OCH.sub.3 H H H H H H 2      ##STR314##      H OCH.sub.3 OCH.sub.3 H Br H H CH.sub.3 CH.sub.3 H H 2      ##STR315##      H OC.sub.2      H.sub.5 H H Cl H CH.sub.3 H H H H 2     ##STR316##                  H OCH.sub.3 OCH.sub.3 OCH.sub.3 H CH.sub.3      ##STR317##      H H H 2      ##STR318##                   H OCH.sub.3 H H CH.sub.3 Cl H H H H H 3      ##STR319##      H OCH.sub.3 H H Cl H H H H H H 3      ##STR320##      H OCH.sub.3 Cl H H H H H H H CH.sub.3 2      ##STR321##      H OCH.sub.3 OCH.sub.3 H CH.sub.3 CH.sub.3 H H H H H 2      ##STR322##      H H OCH.sub.3 H CH.sub.3 H CH.sub.3 H H H CH.sub.3 5      ##STR323##      H CH.sub.3 H H OCH.sub.3 H H H H H CH.sub.3 5      ##STR324##      H H H OCH.sub.3 H H H      ##STR325##      H H CH.sub.3 3      ##STR326##      H OCH.sub.3 H H H H H H H H H 3      ##STR327##      H OCH.sub.3 OCH.sub.3 H CH.sub.3 CH.sub.3 H H H H H 4      ##STR328##     ##STR329##     EXAMPLE 18B  Following procedures similar to those Examples 1-10 and 12     substituting the appropriate 1-haloalkyl-2-benziothiepin for 1-haloalkyl-     2-benzoxepin, 2-benzothiepins with branched-chain amines (Table 12) can     be prepared.

    TABLE 12      ##STR330##                 Branch  R.sub.1 ' R.sub.1 " R.sub.1 "' R.sub.1 "" R.sub.2     R.sub.3 R.sub.4 R.sub.5 R.sub.6 R.sub.7 R.sub.8 Chain NR.sub.9      R.sub.10                 H H C.sub.3 H.sub.7 OCH.sub.3 H H H H H H H      ##STR331##      ##STR332##      H H H OCH.sub.3 H H H H H H H      ##STR333##      ##STR334##      OCH.sub.3 OCH.sub.3 H H H H H H H H H      ##STR335##      ##STR336##      H OC.sub.2      H.sub.5 H H H H H H H H H                                     ##STR337##      ##STR338##      H OCH.sub.3 OCH.sub.3 OCH.sub.3 H H H H H H H      ##STR339##      ##STR340##      H OH OCH.sub.3 H H H H H H H H      ##STR341##      ##STR342##      H OCH.sub.3 Br H H H CH.sub.3 H H H H      ##STR343##      ##STR344##      H OCH.sub.3 Cl Cl H H H H H H H      ##STR345##      ##STR346##      H OCH.sub.3 CF.sub.3 H H H H H H H H      ##STR347##      ##STR348##                  H      ##STR349##      H H H H H H H H      ##STR350##      ##STR351##                   H OCH.sub.3 H H CH.sub.3 H H H H H H      ##STR352##      ##STR353##      H OCH.sub.3 H OCH.sub.3 CH.sub.3 H CH.sub.3 H H H H      ##STR354##      ##STR355##      H OCH.sub.3 OCH.sub.3 OCH.sub.3 H H H CH.sub.3 H H H      ##STR356##      ##STR357##      H H H OCH.sub.3 H H H      ##STR358##      H H H      ##STR359##      ##STR360##      H OH H H H Br H H H H H      ##STR361##      ##STR362##      H OCH.sub.3 OCH.sub.3 H CH.sub.3 CH.sub.3 H H H H CH.sub.3      ##STR363##      ##STR364##      H OCH.sub.3 OCH.sub.3 H H H CH.sub.3 CH.sub.3 H H CH.sub.3      ##STR365##      ##STR366##                 H OCH.sub.3 OCH.sub.3 H H H      ##STR367##      H H CH.sub.3      ##STR368##      ##STR369##                   H OC.sub.3 H.sub.7 OC.sub.3      H.sub.7 H H H H H H H                                     ##STR370##      ##STR371##      ##STR372##

EXAMPLE 19

Following procedures similar to those of Examples 13 through 18, butsubstituting the appropriate(1,3,4,5-tetrahydro-2-benzothiepin-1-yl)alkoxy alkyl halides orbenzenesulfonates for the corresponding benzoxepins, the benzothiepinsof Table 13 can be prepared.

                                      TABLE 13                                    __________________________________________________________________________     ##STR373##                                                                   R.sub.1 '                                                                          R.sub.1 "                                                                          R.sub.1 '"                                                                         R.sub.1 ""                                                                         R.sub.2                                                                          R.sub.3                                                                          R.sub.4                                                                           R.sub.5                                                                           R.sub.6                                                                          R.sub.7                                                                          R.sub.8                                                                          m q NR.sub.21 R.sub.22             __________________________________________________________________________    H    H    propyl                                                                             OCH.sub.3                                                                          H  H  H   H   H  H  H  1 1                                                                                ##STR374##                    H    H    H    OCH.sub.3                                                                          H  H  H   H   H  H  H  1 2                                                                                ##STR375##                    OCH.sub.3                                                                          OCH.sub.3                                                                          H    H    H  H  H   H   H  H  H  1 3                                                                                ##STR376##                    H    OC.sub.2 H.sub.5                                                                   H    H    H  H  H   H   H  H  H  2 1                                                                                ##STR377##                    H    OCH.sub.3                                                                          OCH.sub.3                                                                          OCH.sub.3                                                                          H  H  H   H   H  H  H  2 2                                                                                ##STR378##                    OCH.sub.3                                                                          OH   H    H    H  H  H   H   H  H  H  2 3                                                                                ##STR379##                    H    OCH.sub.3                                                                          Br   H    H  H  H   H   H  H  H  3 1                                                                                ##STR380##                    H    OCH.sub.3                                                                          Cl   Cl   H  H  H   H   H  H  H  3 2                                                                                ##STR381##                    H    OCH.sub.3                                                                          CF.sub.3                                                                           H    H  H  H   H   H  H  H  3 3                                                                                ##STR382##                          ##STR383##                                                                             H    H  H  H   H   H  H  H  1 1                                                                                ##STR384##                    H    OCH.sub.3                                                                          H    H    CH.sub.3                                                                         H  H   H   H  H  H  2 1                                                                                ##STR385##                    H    OCH.sub.3                                                                          H    OCH.sub.3                                                                          CH.sub.3                                                                         H  CH.sub.3                                                                          H   H  H  H  3 2                                                                                ##STR386##                    H    OCH.sub.3                                                                          OCH.sub.3                                                                          OCH.sub.3                                                                          H  H  OCH.sub.3                                                                         CH.sub.3                                                                          H  H  H  2 3                                                                                ##STR387##                    H    H    H    OCH.sub.3                                                                          H  H  H                                                                                  ##STR388##                                                                       H  H  H  1 3                                                                                ##STR389##                    H    OH   H    H    H  Br H   H   H  H  H  1 1                                                                                ##STR390##                    H    OCH.sub.3                                                                          OCH.sub.3                                                                          H    CH.sub.3                                                                         CH.sub.3                                                                         H   H   H  H  H  2 2                                                                                ##STR391##                    H    OCH.sub.3                                                                          OCH.sub.3                                                                          H    H  H  CH.sub.3                                                                          CH.sub.3                                                                          H  H  H  3 3                                                                                ##STR392##                    H    OCH.sub.3                                                                          OCH.sub.3                                                                          H                                                                                   ##STR393##                                                                         H   H   H  H  H  3 1                                                                                ##STR394##                    H    OC.sub.3 H.sub.7                                                                   OC.sub.3 H.sub.7                                                                   H    *  H  *   H   H  H  H  1 1                                                                                ##STR395##                    H    H    OCH.sub.3                                                                          OCH.sub.3                                                                          H  H                                                                                 ##STR396##                                                                       H   H  H  H  1 1                                                                                ##STR397##                    H    OH   OH   H    C.sub.3 H.sub.7                                                                  H  H   H   H  H  H  1 1                                                                                ##STR398##                    H    OCH.sub.3                                                                          OCH.sub.3                                                                          H    H  H  H   H   H  H  CH.sub.3                                                                         1 3 N(CH.sub.3).sub.2              H    OCH.sub.3                                                                          OCH.sub.3                                                                          H    H  H  H   H   H  H  CH.sub.3                                                                         1 3                                                                                ##STR399##                    H    OCH.sub.3                                                                          OCH.sub.3                                                                          H    CH.sub.3                                                                         CH.sub.3                                                                         H   H   H  H  CH.sub.3                                                                         1 4 NH butyl                       H    OCH.sub.3                                                                          OCH.sub.3                                                                          H    H  H  CH.sub.3                                                                          CH.sub.3                                                                          H  H  CH.sub.3                                                                         2 3                                                                                ##STR400##                    H    OCH.sub.3                                                                          OCH.sub.3                                                                          H    CH.sub.3                                                                         CH.sub.3                                                                         H   H   H  H  C.sub.6 H.sub.5                                                                  1 3 NH-t-butyl                     H    OCH.sub.3                                                                          OCH.sub.3                                                                          H    H  H  H   H   H  H  C.sub.6 H.sub.5                                                                  1 3 NH.sub.2                       __________________________________________________________________________     ##STR401##                                                                    -                                                                        

EXAMPLES 20 THROUGH 26 Isochromans and Isothiochromans EXAMPLE 204-(4-chlorophenyl)-1-[(3,4-dihydro-6,7-dimethoxy-4,4-dimethyl-1H-2-benzopyran-1-yl)methyl]-1,2,3,6-tetrahydropyridine,monohydrochloride.

A mixture of 1.52 g of6,7-dimethoxy-4,4-dimethyl-1-bromomethylisochroman, 1.35 g of4-(4-chlorophenyl)-1,2,3,6-tetrahydropyridine, and 2 ml. oftriethylamine in 5 ml of DMF are heated at 50° C. for 23 hr. The mixtureis partitioned between methylene chloride and aqueous potassiumcarbonate. The organic phase is dried over sodium sulfate andconcentrated. The residue is chromatographed over silica gel utilizing5% methanol/1/2% ammonium hydroxide/methylene chloride to give a 21%yield 4-(4-chlorophenyl)-1-[(3,4-dihydro-4,4-dimethyl-6,7-dimethoxy-1H-2-benzopyran-1-yl)methyl]-1,2,3,6-tetrahydropyridine.

The salt is prepared from hydrogen chloride in ether and recrystallizedfrom ethanol/ethyl acetate, mp 250°-252°.

Anal. Calcd for C₂₅ H₃₀ NO₃ Cl.HCl Calcd: C, 64.65; H, 6.73; N, 3.01;Cl, 15.27 Found: C, 63.16; H, 6.78; N, 2.98; Cl, 14.87.

EXAMPLE 21a1-Methyl-1-[3-(3,4-dihydro-6,7-dimethoxy-1H-2-benzopyran-1-yl)propyl]-4-(4-fluorophenyl)-piperazine,dihydrochloride

A solution of1-methyl-1-(3-chloropropyl)-3,4-dihydro-6,7-dimethoxy-1H-2-benzopyran(0.6 g., 0.002 mole), p-fluoropiperazine (0.4 g., 0.002 mole) and 0.5 g.of triethylamine in 10 ml. of ethylene glycol is heated to 80° C. undernitrogen for twenty hours. The reaction mixture is poured into water andextracted with methylene chloride. The methylene chloride solution iswashed with water, a saturated solution of sodium chloride, dried oversodium sulfate and concentrated to an oil. The oil is chromatographed ona silica gel column using 5% methanol/methyl chloride as eluent to yield500 mg. of1-methyl-1-[3-(3,4-dihydro-6,7-dimethoxy-1H-2-benzopyran-1-yl)propyl]-4-(4-fluorophenyl)piperazineas a white oil. This is reacted with ethereal HCl and the productrecrystallized from methanol/ether to yield 300 mg. of1-methyl-1-[3-(3,4-dihydro-6,7-dimethoxy-1H-2-benzopuran-1-yl)propyl]-4-(4-fluorophenyl)piperazine,dihydrochloride, m.p. 240°-242° C.

EXAMPLE 21b1-[2-(6,7-dimethoxy-4,4-dimethylisochroman-1-yl)ethyl]-4-(3-trifluoromethylphenyl)-piperazine,dihydrochloride

A mixture of 1.50 g. (0.0053 m) of2-(6,7-dimethoxy-4,4-dimethyisochroman-1-yl)ethyl chloride, 2.48 g.(0.011 m) of 3-trifluoromethylphenylpiperazine and 30 ml of ethyleneglycol is stirred at 55° for 24 hr. The mixture is partitioned betweenmethylene chloride and sodium bicarbonate. The organic phase isconcentrated and chromatographed. The salt of the title compound isprepared from ethereal hydrogen chloride. The yield is 0.83 g., mp162°-163.5° C.

Anal. Calcd. for C₂₆ H₂₃ N₂ F₃ O₃.2HCl Calcd: C, 56.62; H, 6.39; N,5.08; Cl, 12.86 Found: C, 56.52; H, 6.52; N, 5.02; Cl, 11.25.

EXAMPLE 21c2-[2-[(6,7-dimethoxy-4,4-dimethylisochroman-1-yl)ethyl]]6,7-dimethoxy-1,2,3,4-tetrahydroisoquinoline

A mixture of 2.0 g of[2-(6,7-dimethoxy-4,4-dimethylisochroman-1-yl)ethyl]-[2-(3,4-dimethoxyphenyl)ethyl]amine,500 mg of paraformaldehyde, 25 ml of toluene, and 10 ml of nitrobenzeneis heated at 100° for 4 hours. The mixture is partitioned betweenmethylene chloride and water. The organic phase is concentrated andchromatographed to yield the titled compound which is converted to itshydrogen chloride salt and crystallized from ethyl acetate to give 800mg of the title compound as its salt, mp 100°-105°.

Anal. Calcd. for C₂₆ H₃₅ NO₅.HCl.11/2H₂ O Calcd: C, 61.82; H, 7.38; N,2.77; Cl, 7.03 Found: C, 61.26; H, 7.30; N, 2.90; Cl, 7.03

In the manner of examples 20,21a, and 21b, the following isochromans areprepared from the appropriate (6,7-dimethoxyisochroman-1-yl)alkylhalides and the appropriate amines. (Table 14).

    TABLE 14      ##STR402##      HNR.sub.9 R.sub.10 n R.sub.2 R.sub.3 R.sub.8 °C./Hrs Misc. M.P.     (°C.) Anal. (Found)      Name      ##STR403##      1 CH.sub.3 CH.sub.3 H 50°/23 DMF Solvent 250-252.sup.a C, 63.16;     H, 6.78;N, 2.98; Cl, 14.87 4-(4-chlorophenyl)-1-[(3,4-dihydro-4,4-dimethy     l-6,7-dimethoxy-1H-2-benzopyran-1-yl)-methyl]-1,2,3,6-hydropyridine,     mono-hydrochloride      ##STR404##       2 CH.sub.3 CH.sub.3 H 55°/24  223°(decomp).sup.d C,     60.76; H, 7.77;N, 9.51; Cl, 14.37 1[2-(3,4-dihydro-4,4-dimethyl-6,7-dimet     hoxy-1H-2-benzopyran-1-yl)-ethyl]-4-(2-pyridyl)-piperazine, dihydro-chlor     ide      ##STR405##      2 CH.sub.3 CH.sub.3 H 50°/15  181-5°(dec).sup.a C, 61.37;     H, 7.02;N, 5.93 1-[2-(3,4-dihydro-6,7-dimethoxy-1H-2-benzo-pyran-1-yl)eth     yl]-4-(4-flourophenyl)-piperazine, hydrochlo-ride      ##STR406##      2 CH.sub.3 CH.sub.3 H 55°/18  162-163.5.sup.d C, 56.52; H,     6.52;N, 5.02 1-[2-(3,4-dihydro-6,7-dimethoxy-1H-2-benzo-pyran-1-yl)ethyl]     -4-(3-trifluoromethylphenyl)-piperazine, dihydrochlo-ride      ##STR407##      2 CH.sub.3 CH.sub.3 H 80°/20  198-200 (dec).sup.b 4-(p-chlorophen     yl)-1-61.22; H, 6.93;N, 5.75; Cl 15.24 4-(p-chlorophenyl9-1-[2-(4,4-dimet     hyl)-6,7-dimethoxy-1H-2-benzo-pyran-1-yl)ethyl]pipera-zine, monohydrochlo     ride      ##STR408##      2 CH.sub.3 CH.sub.3 H 80°/20  233-235(dec).sup.d N, 62.28; H,     7.61;N, 5.48; Cl, 12.15 4-(p-methoxyphenyl)-1-[2-(4,4-dimethyl)-6,7-dimet     hoxy-1H-2-benzo-pyran-1-yl)ethyl]-piperazine, dihydrochlo-ride      ##STR409##      2 CH.sub.3 CH.sub.3 H 80°/20  243.0(dec).sup.a C, 67.29; H,      N     7.73;, 6.10; Cl, 7.88 4-(o-tolyl)-1-[2-(4,4-dimethyl)-6,7-dimethoxy-1H-2-     benzopyran-1-yl)-ethyl)piperazine, mono-hydrochloride      ##STR410##      2 CH.sub.3 CH.sub.3 H 80°/20  167-170.sup.b C, 68.72; H, 7.50N,     3.77; Cl, 8.44 4-phenyl-1-[2-(3,4-dihydro-4,4-dimethyl)-6,7-dimethoxy1H-2     -benzopyran-1-yl)ethyl1,2,3,6-tetrahydropyridinemonohydrochloride      ##STR411##      2 CH.sub.3 CH.sub.3 H 80°/20  188-190.sup.e C, 66.8; H, 8.26;N,     6.10 4-phenyl-1-[2-(3,4-dihydro-4,4-dimethyl-6,7-dimethoxy-1H-2-benzopyra     n-1-yl)-ethyl]piperazine      ##STR412##      3 H H CH.sub.3 80°/20   C, 69.63; H, 7.59;N, 8.81 1-[1-[3-(3,4-di     hydro-6,7-dimethoxy-1-methyl-1H-2-benzopyran-1-yl)propyl]-4-piperdinyl]-1     ,3-dihydro-2H-benzimidazol-2-one      ##STR413##      3 H H CH.sub.3 80°/20  197-199 as mono MeOH . 2HClC, 58.31; H,     7.10;N, 8.14; Cl, 13.75; 4-(2-pyridyl)-1-[3-(3,4-dihydro-1-methyl-6,7-dim     ethoxy-1H-2-benzopyran-1-yl)propyl]piperidine      ##STR414##      3 H H      ##STR415##      80°/20  140-142.sup.f C, 60.27; H, 5.92;H, 4.84; Cl, 6.15     4-(4-fluorophenyl)-1-[3-(3,4-dihydro-1-(4-fluoro-phenyl)-6,7-dimethoxy-1H     -2-benzopyran-1-yl)propyl]-piperazine      ##STR416##      3 H H      ##STR417##     80°/20  236-238.sup.c C, 66.35; H, 7.34;N, 5.97; F, 3.33 4-(2-meth     ylphenyl)-1-[3-(3,4-dihydro-1-(4-fluorophenyl)-6,7-dimethoxy-1H-2-benzo-p     yran-1-yl)propyl]piperazin      ##STR418##      3 H H      ##STR419##      80°/20 nmr spectrumis consistentwith assignedstructure. 4-(phenyl     )-1-[3-(3,4-dihydro-1-(4-fluorophenyl)-6,7-dimethoxy-1H-2-benzopyran-1-yl     )propyl]-1,2,3,6-tetra-hydropyridine      ##STR420##      3 H H      ##STR421##      80°/20  153-155.sup.c C, 66.04; H, 6.49;H, 5.25; Cl, 6.67     1-(3-(3,4-dihydro-1-(4-fluorophenyl)-6,7-dimethoxy1H-2-benzopyran-1-yl)pr     opyl4-phenylpiperazine      ##STR422##      3 H H      ##STR423##      80°/20  218-220° C, 69.53; H, 6.31;N, 7.45; F, 3.29     1-[1-[3-(3,4-dohydro-6,7-dimethoxy-1-(4-fluorophenyl1H-2-benzopyran-1-yl)     propyl4-piperidinyl]-1,3-dihydro-2H-benzimidazol-2-one     .sup.a HCl salt     .sup.b HCl salt hemihydrate     .sup.c HCl salt hydrate     .sup.d dihydrochloride salt     .sup.e dihydrate     .sup.f trihydrate hydrochloride

EXAMPLE 22

Following procedures similar to those of Examples 20-21C, butsubstituting the appropriate (isochroman-1-yl)alkyl halides and theappropriate amines, the following compounds can be made.

                                      TABLE 15                                    __________________________________________________________________________     ##STR424##                                                                   R.sub.1 '                                                                          R.sub.1 "                                                                          R.sub.1 '"                                                                         R.sub.1 ""                                                                         R.sub.2                                                                           R.sub.3                                                                           R.sub.4                                                                           R.sub.5                                                                           R.sub.8                                                                               n                                                                              NR.sub.9 R.sub.10                __________________________________________________________________________    H    H    propyl                                                                             OCH.sub.3                                                                          CH.sub.3                                                                          H   H   H   H      1                                                                                ##STR425##                      H    H    H    OCH.sub.3                                                                          CH.sub.3                                                                          H   H   H   H      1                                                                                ##STR426##                      OCH.sub.3                                                                          OCH.sub.3                                                                          H    H    CH.sub.3                                                                          H   H   H   H      1                                                                                ##STR427##                      H    OH   H    H    H   H   F   H   H      4                                                                                ##STR428##                      H    OCH.sub.3                                                                          OCH.sub.3                                                                          H    CH.sub.3                                                                          CH.sub.3                                                                          H   H   H      5                                                                                ##STR429##                      H    OCH.sub.3                                                                          OCH.sub.3                                                                          H    H   H   CH.sub.3                                                                          CH.sub.3                                                                          H      5                                                                                ##STR430##                      H    OCH.sub.3                                                                          OCH.sub.3                                                                          H                                                                                   ##STR431##                                                                           H   H   H      5                                                                                ##STR432##                      H    OC.sub.3 H.sub.7                                                                   OC.sub.3 H.sub.7                                                                   H    C.sub.2 H.sub.5                                                                   H   H                                                                                  ##STR433##                                                                       H      5                                                                                ##STR434##                      H    H    OCH.sub.3                                                                          OCH.sub.3                                                                          C.sub.3 H.sub.7                                                                   H       H   H      2                                                                                ##STR435##                      H    OH   OH   H    C.sub.3 H.sub.7                                                                   H   C.sub.3 H.sub.7                                                                   H   H      2                                                                                ##STR436##                      H    OCH.sub.3                                                                          OCH.sub.3                                                                          CF.sub.3                                                                           C.sub.3 H.sub.7                                                                   H   H   H   H      1                                                                                ##STR437##                      H    OCH.sub.3                                                                          OCH.sub.3                                                                          H    C.sub.3 H.sub. 7                                                                  H   H   H   H      2                                                                                ##STR438##                      H    OCH.sub.3                                                                          OCH.sub.3                                                                          H    C.sub.3 H.sub.7                                                                   H   H   H   H      2                                                                                ##STR439##                      H    OCH.sub.3                                                                          OCH.sub.3                                                                          H    CH.sub.3                                                                          H   H   H   H      2                                                                                ##STR440##                      H    OC.sub.2 H.sub.5                                                                   H    H    C.sub.2 H.sub.5                                                                   H   H   H   H      1                                                                                ##STR441##                      H    OCH.sub.3                                                                          OCH.sub.3                                                                          OCH.sub.3                                                                          C.sub.2 H.sub.5                                                                   H   H   H   H      1                                                                                ##STR442##                      OCH.sub.3                                                                          OH   H    H    C.sub.2 H.sub.5                                                                   H   H   H   H      1                                                                                ##STR443##                      H    OCH.sub.3                                                                          Br   H    C.sub.2 H.sub.5                                                                   H   H   H   H      1                                                                                ##STR444##                      H    OCH.sub.3                                                                          Cl   Cl   C.sub.2 H.sub.5                                                                   H   H   H   H      1                                                                                ##STR445##                      H    OCH.sub.3                                                                          CF.sub.3                                                                           H    CH.sub.3                                                                          H   H   H   H      2                                                                                ##STR446##                            ##STR447##                                                                             H    H   H   H   H   H      3                                                                                ##STR448##                      H    OCH.sub.3                                                                          H    H    CH.sub.3                                                                          H   H   H   H      3                                                                                ##STR449##                      H    OCH.sub.3                                                                          H    OCH.sub.3                                                                          CH.sub.3                                                                          H   CH.sub.3                                                                          H   H      3                                                                                ##STR450##                      H    OCH.sub.3                                                                          OCH.sub.3                                                                          OCH.sub.3                                                                          OCH.sub.3                                                                         H   OCH.sub.3                                                                         H   H      4                                                                                ##STR451##                      H    H    H    OCH.sub.3                                                                          H   H   H                                                                                  ##STR452##                                                                       H      4                                                                                ##STR453##                      H    OCH.sub.3                                                                          OCH.sub.3                                                                          H    CH.sub.3                                                                          H   H   H   H      2                                                                                ##STR454##                      H    OCH.sub.3                                                                          OCH.sub.3                                                                          H    CH.sub.3                                                                          H   H   H   H      2                                                                                ##STR455##                      H    OCH.sub.3                                                                          OCH.sub.3                                                                          H    CH.sub. 3                                                                         H   H   H   H      2                                                                                ##STR456##                      H    OCH.sub.3                                                                          OCH.sub.3                                                                          H    C.sub.2 H.sub.5                                                                   H   H   H   H      2                                                                                ##STR457##                      H                                                                                   ##STR458##                                                                             H    C.sub.2 H.sub.5                                                                   H   H   H   H      2                                                                                ##STR459##                      H    OCH.sub.3                                                                          OCH.sub.3                                                                          H    C.sub.3 H.sub.7                                                                   H   H   H   H      2                                                                                ##STR460##                      H    OCH.sub.3                                                                          OCH.sub.3                                                                          H    CH.sub.3                                                                          H   H   H   H      2                                                                                ##STR461##                      H    OCH.sub.3                                                                          OCH.sub.3                                                                          H    CH.sub.3                                                                          H   CH.sub.3                                                                          H   H      2                                                                                ##STR462##                      H    OCH.sub.3                                                                          OCH.sub.3                                                                          H    OCH.sub.3                                                                         H   OCH.sub.3                                                                         H   H      2                                                                                ##STR463##                      H    OCH.sub.3                                                                          OCH.sub.3                                                                          H    H   H   H                                                                                  ##STR464##                                                                       H      2                                                                                ##STR465##                      H    OCH.sub.3                                                                          OCH.sub.3                                                                          H                                                                                   ##STR466##                                                                       H   F   H   H      2                                                                                ##STR467##                      H    OCH.sub.3                                                                          OCH.sub.3                                                                          H    CH.sub.3                                                                          CH.sub.3                                                                          H   H   H      2                                                                                ##STR468##                      H    OCH.sub.3                                                                          OCH.sub.3                                                                          H                                                                                   ##STR469##                                                                       H   CH.sub.3                                                                          CH.sub.3                                                                          CH.sub.3                                                                             2                                                                                ##STR470##                      H    OCH.sub.3                                                                          OCH.sub.3                                                                          H                                                                                   ##STR471##                                                                           H   H   CH.sub.3                                                                             2                                                                                ##STR472##                      H    OCH.sub.3                                                                          OCH.sub.3                                                                          H    CH.sub.3                                                                          H                                                                                  ##STR473##                                                                       H   CH.sub.3                                                                             2                                                                                ##STR474##                      H    OCH.sub.3                                                                          OCH.sub.3                                                                          H    H   H                                                                                  ##STR475##                                                                       H   CH.sub.3                                                                             3                                                                                ##STR476##                      H    OCH.sub.3                                                                          OCH.sub.3                                                                          H    C.sub.2 H.sub.5                                                                   H   C.sub.3 H.sub.7                                                                   H   CH.sub.2                                                                             2                                                                                ##STR477##                      H    OCH.sub.3                                                                          OCH.sub.3                                                                          H    H   H   H   H   CH.sub.3                                                                             2                                                                                ##STR478##                      H    OCH.sub.3                                                                          OCH.sub.3                                                                          H    H   H   H   H   CH.sub.3                                                                             2                                                                                ##STR479##                      H    OCH.sub.3                                                                          OCH.sub.3                                                                          H    H   H   H   H   CH.sub.3                                                                             2                                                                                ##STR480##                      H    OCH.sub.3                                                                          OCH.sub.3                                                                          H    H   H   H   H   CH.sub.3                                                                             2                                                                                ##STR481##                      H    OCH.sub.3                                                                          OCH.sub.3                                                                          H    H   H   H   H   CH.sub.3                                                                             3                                                                                ##STR482##                      H    OCH.sub.3                                                                          OCH.sub.3                                                                          H    H   H   H   H   CH.sub.3                                                                             4                                                                                ##STR483##                      H    OCH.sub.3                                                                          OCH.sub.3                                                                          H    H   H   H   H   CH.sub.3                                                                             2                                                                                ##STR484##                      H    OCH.sub.3                                                                          OCH.sub.3                                                                          H    H   H   H   H   CH.sub.3                                                                             2                                                                                ##STR485##                      H    OCH.sub.3                                                                          OCH.sub.3                                                                          H    H   H   H   H   CH.sub.3                                                                             2                                                                                ##STR486##                      H                                                                                   ##STR487##                                                                             H    H   H   H   H                                                                                  ##STR488##                                                                          2                                                                                ##STR489##                      H    OCH.sub.3                                                                          OCH.sub.3                                                                          H    CH.sub.3                                                                          H   H   H                                                                                  ##STR490##                                                                          2                                                                                ##STR491##                      H    OCH.sub.3                                                                          OCH.sub.3                                                                          H    CH.sub.3                                                                          H   CH.sub.3                                                                          H                                                                                  ##STR492##                                                                          2                                                                                ##STR493##                      H    OCH.sub.3                                                                          OCH.sub.3                                                                          H    OCH.sub.3                                                                         H   OCH.sub.3                                                                         H                                                                                  ##STR494##                                                                          2                                                                                ##STR495##                      H    OCH.sub.3                                                                          OCH.sub.3                                                                          H    H   H   H                                                                                  ##STR496##                                                                        ##STR497##                                                                          2                                                                                ##STR498##                      H    OCH.sub.3                                                                          OCH.sub.3                                                                          H    H   H   Cl  H                                                                                  ##STR499##                                                                          2                                                                                ##STR500##                      H    OCH.sub.3                                                                          OCH.sub.3                                                                          H    CH.sub.3                                                                          CH.sub.3                                                                          H   H                                                                                  ##STR501##                                                                          2                                                                                ##STR502##                      H    OCH.sub.3                                                                          OCH.sub.3                                                                          H    H   H   CH.sub.3                                                                          CH.sub.3                                                                           ##STR503##                                                                          2                                                                                ##STR504##                      H    OCH.sub.3                                                                          OCH.sub.3                                                                          H    CH.sub.3                                                                          H   H   H                                                                                  ##STR505##                                                                          2                                                                                ##STR506##                      H    OCH.sub.3                                                                          OCH.sub.3                                                                          H    C.sub.2 H.sub.5                                                                   C.sub.2 H.sub.5                                                                   H   H                                                                                  ##STR507##                                                                          2                                                                                ##STR508##                      H    OCH.sub.3                                                                          OCH.sub.3                                                                          H    H   H                                                                                  ##STR509##                                                                       H                                                                                  ##STR510##                                                                          2                                                                                ##STR511##                      H    OCH.sub.3                                                                          OCH.sub.3                                                                          H    H   H   C.sub.3 H.sub.7                                                                   H                                                                                  ##STR512##                                                                             ##STR513##                      H    OCH.sub.3                                                                          OCH.sub.3                                                                          H    CH.sub.3                                                                          CH.sub.3                                                                          H   H   CH.sub.3                                                                             3                                                                                ##STR514##                      H    H    H    OCH.sub.3                                                                          C.sub.2 H.sub.5                                                                   C.sub.2 H.sub.5                                                                   H   H   H      3                                                                                ##STR515##                      H    OCH.sub.3                                                                          OCH.sub.3                                                                          H    C.sub.3 H.sub.7                                                                   C.sub.3 H.sub.7                                                                   H   H   H      3                                                                                ##STR516##                      H    OC.sub.2 H.sub.5                                                                   H    H    CH.sub.3                                                                          C.sub.2 H.sub.5                                                                   H   H   CH.sub.3                                                                             2                                                                                ##STR517##                      OH   H    H    H    C.sub.2 H.sub.5                                                                   C.sub.3 H.sub.7                                                                   H   H   H      3                                                                                ##STR518##                      H    OCH.sub.3                                                                          OCH.sub.3                                                                          H    OCH.sub.3                                                                         H   H   H   H      2                                                                                ##STR519##                      H    OCH.sub.3                                                                          OCH.sub.3                                                                          H    Cl  H   H   H   H      1                                                                                ##STR520##                      H    OCH.sub.3                                                                          CF.sub.3                                                                           H    H   H   H   H   CH.sub.3                                                                             3                                                                                ##STR521##                      H                                                                                   ##STR522##                                                                             H                                                                                   ##STR523##                                                                       H   H   H   H      1                                                                                ##STR524##                      H    OCH.sub.3                                                                          OCH.sub.3                                                                          H    CH.sub.3                                                                          H   H   H   H      1                                                                                ##STR525##                      H    OCH.sub.3                                                                          H    H    H   H   H   H   CH.sub.3                                                                             2                                                                                ##STR526##                      H    OCH.sub.3                                                                          H    H    H   H   H   OCH.sub.3                                                                         H      2                                                                                ##STR527##                      H    OCH.sub.3                                                                          OCH.sub.3                                                                          H    H   H   OCH.sub.3                                                                         CH.sub.3                                                                          H      2                                                                                ##STR528##                      H    OC.sub.2 H.sub.5                                                                   H    H    H   OCH.sub.3                                                                         CH.sub.3                                                                          Cl  H      2                                                                                ##STR529##                      H    OCH.sub.3                                                                          OCH.sub.3                                                                          OCH.sub.3                                                                          H   CH.sub.3                                                                          Cl  H   H      2                                                                                ##STR530##                      H    OCH.sub.3                                                                          H    H    CH.sub.3                                                                          Cl  H   H   H      3                                                                                ##STR531##                      H    OCH.sub.3                                                                          H    H    Cl  H   H   H   H      3                                                                                ##STR532##                      H    OCH.sub.3                                                                          Cl   H    CH.sub.3                                                                          CF.sub.3                                                                          H   H   CH.sub.3                                                                             2                                                                                ##STR533##                      H    OCH.sub.3                                                                          OCH.sub.3                                                                          H    CH.sub.3                                                                          H   H   H   H      2                                                                                ##STR534##                      H    H    OCH.sub.3                                                                          H    CH.sub.3                                                                          H   CH.sub.3                                                                          H   CH.sub.3                                                                             5                                                                                ##STR535##                      H    CH.sub.3                                                                           H    H    OCH.sub.3                                                                         H   OCH.sub.3                                                                         H   CH.sub.3                                                                             5                                                                                ##STR536##                      H    H    H    OCH.sub.3                                                                          H   H   H                                                                                  ##STR537##                                                                       CH.sub.3                                                                             3                                                                                ##STR538##                      H    OCH.sub.3                                                                          H    H    H   H   Br  H   H      3                                                                                ##STR539##                      H    OCH.sub.3                                                                          OCH.sub.3                                                                          H    CH.sub.3                                                                          CH.sub.3                                                                          H   H   H      4                                                                                ##STR540##                      __________________________________________________________________________

EXAMPLE 23

Following procedures similar to those in Examples 20-22, butsubstituting the appropriate [isochroman-1-yl]alkyl halides and theappropriate amines, the following compounds are made.

                                      TABLE 16                                    __________________________________________________________________________     ##STR541##                                                                                                    Branch                                       R.sub.1 '                                                                         R.sub.1 "                                                                         R.sub.1 "'                                                                        R.sub.1 ""                                                                        R.sub.2                                                                          R.sub.3                                                                          R.sub.4                                                                          R.sub.5                                                                          R.sub.8                                                                            Chain         NR.sub.9 R.sub.10              __________________________________________________________________________    H   C.sub.3 H.sub.7                                                                   C.sub.3 H.sub.7                                                                   OCH.sub.3                                                                         CH.sub.3                                                                         H  H  H  H                                                                                   ##STR542##                                                                                  ##STR543##                    H   H   H   OCH.sub.3                                                                         CH.sub.3                                                                         CH.sub.3                                                                         H  H  H                                                                                   ##STR544##                                                                                  ##STR545##                    OCH.sub.3                                                                         OCH.sub.3                                                                         H   H   H  H  CH.sub.3                                                                         CH.sub.3                                                                         H                                                                                   ##STR546##                                                                                  ##STR547##                    H   OC.sub.2 H.sub.5                                                                  H   H   CH.sub.3                                                                         H  H  H  H                                                                                   ##STR548##                                                                                  ##STR549##                    H   OCH.sub.3                                                                         OCH.sub.3                                                                         OCH.sub.3                                                                         CH.sub.3                                                                         CH.sub.3                                                                         H  H  H                                                                                   ##STR550##                                                                                  ##STR551##                    H   OH  OCH.sub.3                                                                         H   CH.sub.3                                                                         H  H  H  H                                                                                   ##STR552##                                                                                  ##STR553##                    H   OCH.sub.3                                                                         Br  H   CH.sub.3                                                                         H  CH.sub.3                                                                         H  H                                                                                   ##STR554##                                                                                  ##STR555##                    H   OCH.sub.3                                                                         Cl  Cl  C.sub.2 H.sub.5                                                                  C.sub.2 H.sub.5                                                                  H  H  H                                                                                   ##STR556##                                                                                  ##STR557##                    H   OCH.sub.3                                                                         CF.sub.3                                                                          H   CH.sub.3                                                                         CH.sub.3                                                                         H  H  H                                                                                   ##STR558##                                                                                  ##STR559##                         ##STR560##                                                                           H                                                                                  ##STR561##                                                                         H  H  H                                                                                   ##STR562##                                                                                  ##STR563##                    H   OCH.sub.3                                                                         H   H   H  H                                                                                 ##STR564##                                                                      H  H                                                                                   ##STR565##                                                                                  ##STR566##                    H   OCH.sub.3                                                                         H   OCH.sub.3                                                                         CH.sub.3                                                                         CH.sub.3                                                                         H  H  H                                                                                   ##STR567##                                                                                  ##STR568##                    H   OCH.sub.3                                                                         OCH.sub.3                                                                         OCH.sub.3                                                                         H  H  CH.sub.3                                                                         CH.sub.3                                                                         H                                                                                   ##STR569##                                                                                  ##STR570##                    H   H   H   OCH.sub.3                                                                         H  H  CH.sub.3                                                                         H  H                                                                                   ##STR571##                                                                                  ##STR572##                    H   OC.sub.3 H.sub.7                                                                  OC.sub.3 H.sub.7                                                                  H   H  H  CH.sub.3                                                                         H                                                                                 ##STR573##                                                                         ##STR574##                                                                                  ##STR575##                    H   OH  H   H   C.sub.2 H.sub.5                                                                  H  H  H  H                                                                                   ##STR576##                                                                                  ##STR577##                    H   OCH.sub.3                                                                         OCH.sub.3                                                                         H                                                                                  ##STR578##                                                                      H  H  H  CH.sub.3                                                                            ##STR579##                                                                                  ##STR580##                    H   OCH.sub.3                                                                         OCH.sub.3                                                                         H                                                                                  ##STR581##                                                                         H  H  CH.sub.3                                                                            ##STR582##                                                                                  ##STR583##                    H   OCH.sub.3                                                                         OCH.sub.3                                                                         H   CH.sub.3                                                                         H  H  H  CH.sub.3                                                                            ##STR584##                                                                                  ##STR585##                    __________________________________________________________________________

EXAMPLE 24

Following the procedures described in Preparation 8, and in Examples 13through 18, but substituting either the appropriate isochroman-1-ylalcohols or [isochroman-1-yl]alkoxyalkyl chlorides, or[isochroman-1-yl]alkoxyalkyl benzenesulfonates, the following compoundsare made (Table 17).

                                      TABLE 17                                    __________________________________________________________________________     ##STR586##                                                                   R.sub.1 '                                                                          R.sub.1 "                                                                          R.sub.1 "'                                                                         R.sub.1 ""                                                                         R.sub.2                                                                           R.sub.3                                                                          R.sub.4                                                                           R.sub.5                                                                          R.sub.8                                                                          m q NR.sub.21 R.sub.22                   __________________________________________________________________________    H    H    propyl                                                                             OCH.sub.3                                                                          H   H  H   H  H  1 1                                                                                ##STR587##                          H    H    H    OCH.sub.3                                                                          H   H  H   H  H  1 2                                                                                ##STR588##                          OCH.sub.3                                                                          OCH.sub.3                                                                          H    H    H   H  H   H  H  1 3                                                                                ##STR589##                          H    OC.sub.2 H.sub.5                                                                   H    H    H   H  H   H  H  2 1                                                                                ##STR590##                          H    OCH.sub.3                                                                          OCH.sub.3                                                                          OCH.sub.3                                                                          H   H  H   H  H  2 2                                                                                ##STR591##                          OCH.sub.3                                                                          OH   H    H    H   H  H   H  H  2 3                                                                                ##STR592##                          H    OCH.sub.3                                                                          Br   H    H   H  H   H  H  3 1                                                                                ##STR593##                          H    OCH.sub.3                                                                          Cl   Cl   H   H  H   H  H  3 2                                                                                ##STR594##                          H    OCH.sub.3                                                                          CF.sub.3                                                                           H    H   H  H   H  H  3 3                                                                                ##STR595##                                ##STR596##                                                                             H    H   H  H   H  H  1 1                                                                                ##STR597##                          H    OCH.sub.3                                                                          H    H    CH.sub.3                                                                          H  H   H  H  2 1                                                                                ##STR598##                          H    OCH.sub.3                                                                          H    OCH.sub.3                                                                          CH.sub.3                                                                          H  CH.sub.3                                                                          H  H  3 2                                                                                ##STR599##                          H    OCH.sub.3                                                                          OCH.sub.3                                                                          OCH.sub.3                                                                          OCH.sub.3                                                                         H  OCH.sub.3                                                                         H  H  2 3                                                                                ##STR600##                          H    H    H    OCH.sub.3                                                                          H   H  H                                                                                  ##STR601##                                                                      H  1 3                                                                                ##STR602##                          H    OH   H    H    H   H  F   H  H  1 1                                                                                ##STR603##                          H    OCH.sub.3                                                                          OCH.sub.3                                                                          H    CH.sub.3                                                                          CH.sub.3                                                                         H   H  H  2 2                                                                                ##STR604##                          H    OCH.sub.3                                                                          OCH.sub.3                                                                          H    H   H  CH.sub.3                                                                          CH.sub.3                                                                         H  3 3                                                                                ##STR605##                          H    OCH.sub.3                                                                          OCH.sub.3                                                                          H                                                                                   ##STR606##                                                                          H   H  H  3 1                                                                                ##STR607##                          H    OC.sub.3 H.sub.7                                                                   OC.sub.3 H.sub.7                                                                   H    H   H                                                                                 ##STR608##                                                                       H  H  1 1                                                                                ##STR609##                          H    H    OCH.sub.3                                                                          OCH.sub.3                                                                          H   H                                                                                 ##STR610##                                                                       H  H  1 1                                                                                ##STR611##                          H    OH   OH   H    H   H  C.sub.3 H.sub.7                                                                   H  H  1 1                                                                                ##STR612##                          H    OCH.sub.3                                                                          OCH.sub.3                                                                          H    H   H  CH.sub.3                                                                          H  CH.sub.3                                                                         1 3 N(CH.sub.3).sub.2                    H    OCH.sub.3                                                                          OCH.sub.3                                                                          H    C.sub.2 H.sub.5                                                                   H  H   H  CH.sub.3                                                                         1 4                                                                                ##STR613##                          H    OCH.sub.3                                                                          OCH.sub.3                                                                          H                                                                                   ##STR614##                                                                       H  H   H  CH.sub.3                                                                         1 4 NH butyl                             H    OCH.sub.3                                                                          OCH.sub.3                                                                          H                                                                                   ##STR615##                                                                          H   H  CH.sub.3                                                                         2 3                                                                                ##STR616##                          H    OCH.sub.3                                                                          OCH.sub.3                                                                          H    CH.sub.3                                                                          H  H   H  C.sub.6 H.sub.5                                                                  1 3 NHt-butyl                            H    OCH.sub.3                                                                          OCH.sub.3                                                                          H    H   H  CH.sub.3                                                                          H  C.sub.6 H.sub.5                                                                  1 3 NH.sub.2                             __________________________________________________________________________

EXAMPLE 254-(4-Chlorophenyl)-1-[2-(3,4-dihydro-4,4-dimethyl-6,7-dimethoxy-1H-2-benzothiopyran-1-yl)-methyl]-1,2,3,6-tetrahydropyridine,monohydrochloride

A mixture of 4-(4-chlorophenyl)-1,2,3,6-tetrahydropyridine and(3,4-dihydro-4,4-dimethyl-6,7-dimethoxy-1H-2-benzothiopyran-1-yl)methylchloride are heated in toluene. The mixture is partitioned betweenmethyline chloride and sodium carbonate. The product stated above isisolated from the organic phase by chromatography and crystallization.

EXAMPLE 26

Following the procedures similar to those used in Examples 20-22 and 25,but substituting the appropriate (isothiochroman-1-yl)alkyl halide for(isochroman-1-yl)alkyl halide and the appropriate amines, the followingcompounds can be prepared (Table 18).

                                      TABLE 18                                    __________________________________________________________________________     ##STR617##                                                                   R.sub.1 '                                                                          R.sub.1 "                                                                          R.sub.1 "'                                                                         R.sub.1 ""                                                                         R.sub.2                                                                           R.sub.3                                                                           R.sub.4                                                                            R.sub.5                                                                            R.sub.8                                                                              n NR.sub.9 R.sub.10              __________________________________________________________________________    H    H    propyl                                                                             OCH.sub.3                                                                          CH.sub.3                                                                          H   H    H    H      1                                                                                ##STR618##                    H    H    H    OCH.sub.3                                                                          CH.sub.3                                                                          H   H    H    H      1                                                                                ##STR619##                    OCH.sub.3                                                                          OCH.sub.3                                                                          H    H    CH.sub.3                                                                          H   H    H    H      1                                                                                ##STR620##                    H    OH   H    H    H   H   F    H    H      4                                                                                ##STR621##                    H    OCH.sub.3                                                                          OCH.sub.3                                                                          H    CH.sub.3                                                                          H   H    H    5                                                                                     ##STR622##                      H    OCH.sub.3                                                                          OCH.sub.3                                                                          H    H   H   CH.sub.3                                                                           CH.sub.3                                                                           H      5                                                                                ##STR623##                    H    OCH.sub.3                                                                          OCH.sub.3                                                                          H                                                                                   ##STR624##                                                                           H    H    H      5                                                                                ##STR625##                    H    OC.sub.3 H.sub.7                                                                   OC.sub.3 H.sub.7                                                                   H    C.sub.2 H.sub.5                                                                   H   H                                                                                   ##STR626##                                                                        H      5                                                                                ##STR627##                    H    H    OCH.sub.3                                                                          OCH.sub.3                                                                          C.sub.3 H.sub.7                                                                   H        H    H      2                                                                                ##STR628##                    H    OH   OH   H    C.sub.3 H.sub.7                                                                   H   C.sub.3 H.sub.7                                                                    H    H      2                                                                                ##STR629##                    H    OCH.sub.3                                                                          OCH.sub.3                                                                          CF.sub.3                                                                           C.sub.3 H.sub.7                                                                   H   H    H    H      1                                                                                ##STR630##                    H    OCH.sub.3                                                                          OCH.sub.3                                                                          H    C.sub.3 H.sub.7                                                                   H   H    H    H      2                                                                                ##STR631##                    H    OCH.sub.3                                                                          OCH.sub.3                                                                          H    C.sub.3 H.sub.7                                                                   H   H    H    H      2                                                                                ##STR632##                    H    OCH.sub.3                                                                          OCH.sub.3                                                                          H    CH.sub.3                                                                          H   H    H    H      2                                                                                ##STR633##                    H    OC.sub.2 H.sub.5                                                                   H    H    C.sub.2 H.sub.5                                                                   H   H    H    H      1                                                                                ##STR634##                    H    OCH.sub.3                                                                          OCH.sub.3                                                                          OCH.sub.3                                                                          C.sub.2 H.sub.5                                                                   H   H    H    H      1                                                                                ##STR635##                    OCH.sub.3                                                                          OH   H    H    C.sub.2 H.sub.5                                                                   H   H    H    H      1                                                                                ##STR636##                    H    OCH.sub.3                                                                          Br   H    C.sub.2 H.sub.5                                                                   H   H    H    H      1                                                                                ##STR637##                    H    OCH.sub.3                                                                          Cl   Cl   C.sub.2 H.sub.5                                                                   H   H    H    H      1                                                                                ##STR638##                    H    OCH.sub.3                                                                          CF.sub.3                                                                           H    CH.sub.3                                                                          H   H    H    H      2                                                                                ##STR639##                          ##STR640##                                                                             H    H   H   H    H    H      3                                                                                ##STR641##                    H    OCH.sub.3                                                                          H    H    CH.sub.3                                                                          H   H    H    H      3                                                                                ##STR642##                    H    OCH.sub.3                                                                          H    OCH.sub.3                                                                          CH.sub.3                                                                          H   CH.sub.3                                                                           H    H      3                                                                                ##STR643##                    H    OCH.sub.3                                                                          OCH.sub.3                                                                          OCH.sub.3                                                                          OCH.sub.3                                                                         H   OCH.sub.3                                                                          H    H      4                                                                                ##STR644##                    H    H    H    OCH.sub.3                                                                          H   H   H                                                                                   ##STR645##                                                                        H      4                                                                                ##STR646##                    H    OCH.sub.3                                                                          OCH.sub.3                                                                          H    CH.sub.3                                                                          H   H    H    H      2                                                                                ##STR647##                    H    OCH.sub.3                                                                          OCH.sub.3                                                                          H    CH.sub.3                                                                          H   H    H    H      2                                                                                ##STR648##                    H    OCH.sub.3                                                                          OCH.sub.3                                                                          H    CH.sub.3                                                                          H   H    H    H      2                                                                                ##STR649##                    H    OCH.sub.3                                                                          OCH.sub.3                                                                          H    C.sub.2 H.sub.5                                                                   H   H    H    H      2                                                                                ##STR650##                    H                                                                                   ##STR651##                                                                             H    C.sub.2 H.sub.5                                                                   H   H    H    H      2                                                                                ##STR652##                    H    OCH.sub.3                                                                          OCH.sub.3                                                                          H    C.sub.3 H.sub.7                                                                   H   H    H    H      2                                                                                ##STR653##                    H    OCH.sub.3                                                                          OCH.sub.3                                                                          H    CH.sub.3                                                                          H   H    H    H      2                                                                                ##STR654##                    H    OCH.sub.3                                                                          OCH.sub.3                                                                          H    CH.sub.3                                                                          H   CH.sub.3                                                                           H    H      2                                                                                ##STR655##                    H    OCH.sub.3                                                                          OCH.sub.3                                                                          H    OCH.sub.3                                                                         H   OCH.sub.3                                                                          H    H      2                                                                                ##STR656##                    H    OCH.sub.3                                                                          OCH.sub.3                                                                          H    H   H   H                                                                                   ##STR657##                                                                        H      2                                                                                ##STR658##                    H    OCH.sub.3                                                                          OCH.sub.3                                                                          H                                                                                   ##STR659##                                                                       H   F    H    H      2                                                                                ##STR660##                    H    OCH.sub.3                                                                          OCH.sub.3/ H                                                                       CH.sub.3                                                                           CH.sub.3                                                                          H   H    H    2                                                                                     ##STR661##                      H    OCH.sub.3                                                                          OCH.sub.3                                                                          H                                                                                   ##STR662##                                                                       H   CH.sub.3                                                                           CH.sub.3                                                                           CH.sub.3                                                                             2                                                                                ##STR663##                    H    OCH.sub.3                                                                          OCH.sub. 3                                                                         H                                                                                   ##STR664##                                                                       H        H    CH.sub.3                                                                             2                                                                                ##STR665##                    H    OCH.sub.3                                                                          OCH.sub.3                                                                          H    CH.sub.3                                                                          H                                                                                  ##STR666##                                                                        H    CH.sub.3                                                                             2                                                                                ##STR667##                    H    OCH.sub.3                                                                          OCH.sub.3                                                                          H    H   H                                                                                  ##STR668##                                                                        H    CH.sub.3                                                                             3                                                                                ##STR669##                    H    OCH.sub.3                                                                          OCH.sub.3                                                                          H    C.sub.2 H.sub.5                                                                   H   C.sub.3 H.sub.7                                                                    H    CH.sub.3                                                                             2                                                                                ##STR670##                    H    OCH.sub.3                                                                          OCH.sub.3                                                                          H    CH.sub.3                                                                          H   CH.sub.3                                                                           H                                                                                   ##STR671##                                                                          2                                                                                ##STR672##                    H    OCH.sub.3                                                                          OCH.sub.3                                                                          H    OCH.sub.3                                                                         H   OCH.sub.3                                                                          H                                                                                   ##STR673##                                                                          2                                                                                ##STR674##                    H    OCH.sub.3                                                                          OCH.sub.3                                                                          H    H   H   H                                                                                   ##STR675##                                                                         ##STR676##                                                                          2                                                                                ##STR677##                    H    OCH.sub.3                                                                          OCH.sub.3                                                                          H    H   H   Cl   H                                                                                   ##STR678##                                                                          2                                                                                ##STR679##                    H    OCH.sub.3                                                                          OCH.sub.3                                                                          H    CH.sub.3                                                                          CH.sub.3                                                                          H    H                                                                                   ##STR680##                                                                          2                                                                                ##STR681##                    H    OCH.sub.3                                                                          OCH.sub.3                                                                          H    H   H   H    H    CH.sub.3                                                                             2                                                                                ##STR682##                    H    OCH.sub.3                                                                          OCH.sub.3                                                                          H    H   H   H    H    CH.sub.3                                                                             2                                                                                ##STR683##                    H    OCH.sub.3                                                                          OCH.sub.3                                                                          H    H   H   H    H    CH.sub.3                                                                             2                                                                                ##STR684##                    H                                                                                   ##STR685##                                                                             H    H   H   H    H                                                                                   ##STR686##                                                                          2                                                                                ##STR687##                    H    OCH.sub.3                                                                          OCH.sub.3                                                                          H    CH.sub.3                                                                          H   H    H                                                                                   ##STR688##                                                                          2                                                                                ##STR689##                    H    OCH.sub.3                                                                          OCH.sub.3                                                                          H    H   H   H    H    CH.sub.3                                                                             2                                                                                ##STR690##                    H    OCH.sub.3                                                                          OCH.sub.3                                                                          H    H   H   H    H    CH.sub.3                                                                             2                                                                                ##STR691##                    H    OCH.sub.3                                                                          OCH.sub.3                                                                          H    H   H   H    H    CH.sub.3                                                                             2                                                                                ##STR692##                    H    OCH.sub.3                                                                          OCH.sub.3                                                                          H    H   H   H    H    CH.sub.3                                                                             2                                                                                ##STR693##                    H    OCH.sub.3                                                                          OCH.sub.3                                                                          H    H   H   H    H    CH.sub.3                                                                             3                                                                                ##STR694##                    H    OCH.sub.3                                                                          OCH.sub.3                                                                          H    H   H   H    H    CH.sub.3                                                                             4                                                                                ##STR695##                    H    OCH.sub.3                                                                          OCH.sub.3                                                                          H    H   H   CH.sub.3                                                                           CH.sub.3                                                                            ##STR696##                                                                          2                                                                                ##STR697##                    H    OCH.sub.3                                                                          OCH.sub.3                                                                          H    CH.sub.3                                                                          H   H    H                                                                                   ##STR698##                                                                          2                                                                                ##STR699##                    H    OCH.sub.3                                                                          OCH.sub.3                                                                          H    C.sub.2 H.sub.5                                                                   C.sub.2 H.sub.5                                                                   H    H                                                                                   ##STR700##                                                                          2                                                                                ##STR701##                    H    OCH.sub.3                                                                          OCH.sub.3                                                                          H    H   H                                                                                  ##STR702##                                                                        H                                                                                   ##STR703##                                                                          2                                                                                ##STR704##                    H    OCH.sub.3                                                                          OCH.sub.3                                                                          H    H   H   C.sub.3 H.sub.7                                                                    H                                                                                   ##STR705##                                                                           ##STR706##                      H    OCH.sub.3                                                                          OCH.sub.3                                                                          H    CH.sub.3                                                                          CH.sub.3                                                                          H    H    CH.sub.3                                                                             3                                                                                ##STR707##                    H    H    H    OCH.sub.3                                                                          C.sub.2 H.sub.5                                                                   C.sub.2 H.sub.5                                                                   H    H    H      3                                                                                ##STR708##                    H    OCH.sub.3                                                                          OCH.sub.3                                                                          H    C.sub.3 H.sub.7                                                                   C.sub.3 H.sub.7                                                                   H    H    H      3                                                                                ##STR709##                    H    OC.sub.2 H.sub.5                                                                   H    H    CH.sub.3                                                                          C.sub.2 H.sub.5                                                                   H    H    CH.sub.3                                                                             2                                                                                ##STR710##                    OH   H    H    H    C.sub.2 H.sub.5                                                                   C.sub.3 H.sub.7                                                                   H    H    H      3                                                                                ##STR711##                    H    OCH.sub.3                                                                          OCH.sub.3                                                                          H    OCH.sub.3                                                                         H   H    H    H      2                                                                                ##STR712##                    H    OCH.sub.3                                                                          OCH.sub.3                                                                          H    Cl  H   H    H    H      1                                                                                ##STR713##                    H    OCH.sub.3                                                                          CF.sub.3                                                                           H    H   H   H    H    CH.sub.3                                                                             3                                                                                ##STR714##                    H                                                                                   ##STR715##                                                                             H                                                                                   ##STR716##                                                                       H   H    H    H      1                                                                                ##STR717##                    H    OCH.sub.3                                                                          OCH.sub.3                                                                          H    CH.sub. 3                                                                         H   H    H    H      1                                                                                ##STR718##                    H    OCH.sub.3                                                                          H    H    H   H   H    H    CH.sub.3                                                                             2                                                                                ##STR719##                    H    OCH.sub.2                                                                          H    H    H   H   H    OCH.sub.3                                                                          H      2                                                                                ##STR720##                    H    OCH.sub.3                                                                          OCH.sub.3                                                                          H    H   H   OCH.sub.3                                                                          CH.sub.3                                                                           H      2                                                                                ##STR721##                    H    OC.sub.2 H.sub.5                                                                   H    H    H   OCH.sub.3                                                                         CH.sub.3                                                                           Cl   H      2                                                                                ##STR722##                    H    OCH.sub.3                                                                          OCH.sub.3                                                                          OCH.sub.3                                                                          H   CH.sub.3                                                                          Cl   H    H      2                                                                                ##STR723##                    H    OCH.sub.3                                                                          H    H    CH.sub.3                                                                          Cl  H    H    H      3                                                                                ##STR724##                    H    OCH.sub.3                                                                          H    H    Cl  H   H    H    H      3                                                                                ##STR725##                    H    OCH.sub.3                                                                          Cl   H    CH.sub.3                                                                          CF.sub.3                                                                          H    H    CH.sub.3                                                                             2                                                                                ##STR726##                    H    OCH.sub.3                                                                          OCH.sub.3                                                                          H    CH.sub.3                                                                          H   H    H    H      2                                                                                ##STR727##                    H    H    OCH.sub.3                                                                          H    CH.sub.3                                                                          H   CH.sub.3                                                                           H    CH.sub.3                                                                             5                                                                                ##STR728##                    H    CH.sub.3                                                                           H    H    OCH.sub.3                                                                         H   OCH.sub.3                                                                          H    CH.sub.3                                                                             5                                                                                ##STR729##                    H    H    H    OCH.sub.3                                                                          H   H   H                                                                                   ##STR730##                                                                        CH.sub.3                                                                             3                                                                                ##STR731##                    H    OCH.sub. 3                                                                         H    H    H   H   Br   H    H      3                                                                                ##STR732##                    H    OCH.sub.3                                                                          OCH.sub.3                                                                          H    CH.sub.3                                                                          CH.sub.3                                                                          H    H    H      4                                                                                ##STR733##                    __________________________________________________________________________

EXAMPLE 27

Following the procedures similar to those used in Examples 22-23 and 25,but substituting the appropriate (isothiochroman-1-yl)alkyl halides for(isochroman-1-yl)alkyl halides, and the appropriate amines, thefollowing compounds can be made (Table 19).

                                      TABLE 19                                    __________________________________________________________________________     ##STR734##                                                                                                    Branch                                       R.sub.1 '                                                                         R.sub.1 "                                                                         R.sub.1 "'                                                                        R.sub.1 ""                                                                        R.sub.2                                                                          R.sub.3                                                                          R.sub.4                                                                          R.sub.5                                                                          R.sub.8                                                                            Chain        NR.sub.9 R.sub.10               __________________________________________________________________________    H   C.sub.3 H.sub.7                                                                   C.sub.3 H.sub.7                                                                   OCH.sub.3                                                                         CH.sub.3                                                                         H  H  H  H                                                                                   ##STR735##                                                                                 ##STR736##                     H   H   H   OCH.sub.3                                                                         CH.sub.3                                                                         CH.sub.3                                                                         H  H  H                                                                                   ##STR737##                                                                                 ##STR738##                     OCH.sub.3                                                                         OCH.sub.3                                                                         H   H   H  H  CH.sub.3                                                                         CH.sub.3                                                                         H                                                                                   ##STR739##                                                                                 ##STR740##                     H   OC.sub.2 H.sub.5                                                                  H   H   CH.sub.3                                                                         H  H  H  H                                                                                   ##STR741##                                                                                 ##STR742##                     H   OCH.sub.3                                                                         OCH.sub.3                                                                         OCH.sub.3                                                                         CH.sub.3                                                                         CH.sub.3                                                                         H  H  H                                                                                   ##STR743##                                                                                 ##STR744##                     H   OH  OCH.sub.3                                                                         H   CH.sub.3                                                                         H  H  H  H                                                                                   ##STR745##                                                                                 ##STR746##                     H   OCH.sub.3                                                                         Br  H   CH.sub.3                                                                         H  CH.sub.3                                                                         H  H                                                                                   ##STR747##                                                                                 ##STR748##                     H   OCH.sub.3                                                                         Cl  Cl  C.sub.2 H.sub.5                                                                  C.sub.2 H.sub.5                                                                  H  H  H                                                                                   ##STR749##                                                                                 ##STR750##                     H   OCH.sub.3                                                                         CF.sub.3                                                                          H   CH.sub. 3                                                                        CH.sub.3                                                                         H  H  H                                                                                   ##STR751##                                                                                 ##STR752##                          ##STR753##                                                                           H                                                                                  ##STR754##                                                                         H  H  H                                                                                   ##STR755##                                                                                 ##STR756##                     H   OCH.sub.3                                                                         H   H   H  H                                                                                 ##STR757##                                                                      H  H                                                                                   ##STR758##                                                                                 ##STR759##                     H   OCH.sub.3                                                                         H   OCH.sub.3                                                                         CH.sub. 3                                                                        CH.sub.3                                                                         H  H  H                                                                                   ##STR760##                                                                                 ##STR761##                     H   OCH.sub.3                                                                         OCH.sub.3                                                                         OCH.sub.3                                                                         H  H  CH.sub.3                                                                         CH.sub.3                                                                         H                                                                                   ##STR762##                                                                                 ##STR763##                     H   H   H   OCH.sub.3                                                                         H  H  CH.sub.3                                                                         H  H                                                                                   ##STR764##                                                                                 ##STR765##                     H   OH  H   H   C.sub.2 H.sub.5                                                                  H  H  H  H                                                                                   ##STR766##                                                                                 ##STR767##                     H   OCH.sub.3                                                                         OCH.sub.3                                                                         H                                                                                  ##STR768##                                                                      H  H  H  CH.sub.3                                                                            ##STR769##                                                                                 ##STR770##                     H   OCH.sub.3                                                                         OCH.sub.3                                                                         H                                                                                  ##STR771##                                                                         H  H  CH.sub.3                                                                            ##STR772##                                                                                 ##STR773##                     H   OCH.sub.3                                                                         OCH.sub.3                                                                         H   Me H  H  H  CH.sub.3                                                                            ##STR774##                                                                                 ##STR775##                     H   OC.sub.3 H.sub.7                                                                  OC.sub.3 H.sub.7                                                                  H   H  H  Me H                                                                                 ##STR776##                                                                         ##STR777##                                                                                 ##STR778##                     __________________________________________________________________________

EXAMPLE 281-[2-{(1-methyl-6,7-dimethoxy-3,4-dihydro-1H-2-benzothiopyran-1-yl)methoxy}ethyl]piperidine.

A mixture of2-[[1-methyl-6,7-dimethoxy-3,4-dihydro-1H-2-benzothiopyran-1-yl]methoxy]ethanol-4-nitrobenzenesulfonateand piperidine is stirred at room temperature in THF. The mixture isthen partitioned between methylene chloride and aqueous sodiumcarbonate. The title compound is isolated by chromatography and iscrystallized.

The compounds of Table 20 can be prepared using the procedures ofExamples 13-18, 19, and 24 starting from the appropriate[3,4-dihydro-1H-2-benzothiopyran-1-yl]alkoxy alkanols or theirbenzenesulfonates, or the corresponding chlorides and the appropriateamines.

                                      TABLE 20                                    __________________________________________________________________________     ##STR779##                                                                   R.sub.1 '                                                                          R.sub.1 "                                                                          R.sub.1 "'                                                                         R.sub.1 ""                                                                         R.sub.2                                                                           R.sub.3                                                                          R.sub.4                                                                          R.sub.5                                                                           R.sub.8                                                                          m q NR.sub.21 R.sub.22                   __________________________________________________________________________    H    H    propyl                                                                             OCH.sub.3                                                                          H   H  H  H   H  1 1                                                                                ##STR780##                          H    H    H    OCH.sub.3                                                                          H   H  H  H   H  1 2                                                                                ##STR781##                          OCH.sub.3                                                                          OCH.sub.3                                                                          H    H    H   H  H  H   H  1 3                                                                                ##STR782##                          H    OC.sub.2 H.sub.5                                                                   H    H    H   H  H  H   H  2 1                                                                                ##STR783##                          H    OCH.sub.3                                                                          OCH.sub.3                                                                          OCH.sub.3                                                                          H   H  H  H   H  2 2                                                                                ##STR784##                          OCH.sub.3                                                                          OH   H    H    H   H  H  H   H  2 3                                                                                ##STR785##                          H    OCH.sub.3                                                                          Br   H    H   H  H  H   H  3 1                                                                                ##STR786##                          H    OCH.sub.3                                                                          Cl   Cl   H   H  H  H   H  3 2                                                                                ##STR787##                          H    OCH.sub.3                                                                          CF.sub.3                                                                           H    H   H  H  H   H  3 3                                                                                ##STR788##                                ##STR789##                                                                             H    H   H  H  H   H  1 1                                                                                ##STR790##                          H    OCH.sub.3                                                                          H    H    CH.sub.3                                                                          H  H  H   H  2 1                                                                                ##STR791##                          H    OCH.sub.3                                                                          H    OCH.sub.3                                                                          CH.sub.3                                                                          H  CH.sub.3                                                                         H   H  3 2                                                                                ##STR792##                          H    OCH.sub.3                                                                          OCH.sub.3                                                                          OCH.sub.3                                                                          OCH.sub.3                                                                         H  OCH.sub.3                                                                        H   H  2 3                                                                                ##STR793##                          H    H    H    OCH.sub.3                                                                          H   H  H                                                                                 ##STR794##                                                                       H  1 3                                                                                ##STR795##                          H    OH   H    H    H   H  F  H   H  1 1                                                                                ##STR796##                          H    OCH.sub.3                                                                          OCH.sub.3                                                                          H    CH.sub.3                                                                          CH.sub.3                                                                         H  H   H  2 2                                                                                ##STR797##                          H    OCH.sub.3                                                                          OCH.sub.3                                                                          H    H   H  CH.sub.3                                                                         CH.sub.3                                                                          H  3 3                                                                                ##STR798##                          H    OCH.sub.3                                                                          OCH.sub.3                                                                          H                                                                                   ##STR799##                                                                          H  H   H  3 1                                                                                ##STR800##                          H    OC.sub.3 H.sub.7                                                                   OC.sub.3 H.sub.7                                                                   H    H   H                                                                                 ##STR801##                                                                      H   H  1 1                                                                                ##STR802##                          H    H    OCH.sub.3                                                                          OCH.sub.3                                                                          H   H                                                                                 ##STR803##                                                                      H   H  1 1                                                                                ##STR804##                          H    OH   OH   H    H   H  C.sub.3 H.sub.7                                                                  H   H  1 1                                                                                ##STR805##                          H    OCH.sub.3                                                                          OCH.sub.3                                                                          H    H   H  CH.sub.3                                                                         H   CH.sub.3                                                                         1 3 N(CH.sub.3).sub.2                    H    OCH.sub.3                                                                          OCH.sub.3                                                                          H    C.sub.2 H.sub.5                                                                   H  H  H   CH.sub.3                                                                         1 4                                                                                ##STR806##                          H    OCH.sub.3                                                                          OCH.sub.3                                                                          H                                                                                   ##STR807##                                                                       H  H  H   CH.sub.3                                                                         1 4 NH butyl                             H    OCH.sub.3                                                                          OCH.sub.3                                                                          H                                                                                   ##STR808##                                                                          H  H   CH.sub.3                                                                         2 3                                                                                ##STR809##                          H    OCH.sub.3                                                                          OCH.sub.3                                                                          H    CH.sub.3                                                                          H  H  H   C.sub.6 H.sub.5                                                                  1 3 NHt-butyl                            H    OCH.sub.3                                                                          OCH.sub.3                                                                          H    H   H  CH.sub.3                                                                         H   C.sub.6 H.sub.5                                                                  1 3 NH.sub.2                             __________________________________________________________________________

EXAMPLE 29

A lot of 10,000 tablets, each containing 25 mg of1-[2-(6,7-dimethoxy-4,4-dimethylisochroman-1-yl)ethyl]-4-(2-methyl)piperazineis prepared from the following types and amounts of ingredients:

    ______________________________________                                        1-[2-(6,7-dimethoxy-4,4-dimethylisochroman-1-yl)ethyl]-                       4-(2-methylphenyl)piperazine                                                                              250     g                                         Dicalcium phosphate         1000    g                                         Methylcellulose, U.S.P (15 cps)                                                                           60      g                                         Talc                        150     g                                         Corn Starch                 200     g                                         Magnesium stearate          10      g                                         ______________________________________                                    

The compound and dicalcium phosphate are mixed well, granulated with 7.5percent solution of methyl cellulose in water, passed through a No. 8screen and dried carefully. The dried granules are passed through a No.12 screen, mixed thoroughly with the talc, starch and magnesiumstearate, and compressed into tablets.

These tablets are useful in treating hypertension at a dose of twotablets per day.

EXAMPLE 30

A lot of 10,000 tablets, each containing 50 mg ofN-[(7,8-dimethoxy-2-benzoxepin-1-yl)methyl]-(6,7-dimethoxy-1,2,3,4-tetrahydroquinoline)is prepared from the following types and amounts of ingredients

    ______________________________________                                        N-[(7,8-dimethoxy-2-benzoxepin-1-yl)methyl]-(6,7-dime-                        thoxy-1,2,3,4-tetrahydroquinoline)                                                                        500     g                                         Dicalcium Phosphate         1000    g                                         Methylcellulose, U.S.P. (15 cps)                                                                          60      g                                         Talc                        150     g                                         Corn starch                 200     g                                         Magnesium stearate          10      g                                         ______________________________________                                    

The compound and dicalcium phosphate are mixed well, granulated with 7.5percent solution of methyl cellulose in water, passed through a No. 8screen and dried carefully. The dried granules are passed through a No.12 screen, mixed thoroughly with the talc, starch and magnesiumstearate, and compressed into tablets.

These tablets are useful in treating CNS disorders, particularlypsychosis, at a dose of one tablet every eight hours.

EXAMPLE 31

A sterile preparation suitable for intramuscular injection andcontaining 25 mg of1-[2-(6,7-dimethoxy-4,4-dimethylisochroman-1-yl)ethyl]-4-(2-methylphenyl)piperazinehydrochloride in each milliliter is prepared from the following typesand amounts of ingredients:

    ______________________________________                                        1-[2-(6,7-dimethoxy-4-dimethylisochroman-1-yl)ethyl]-                         4-(2-methylphenyl)piperazine hydrochloride                                                               25     g                                           Benzyl benzoate            200    ml                                          Methylparaben              1.5    g                                           Propylparaben              0.5    g                                           Cottonseed oil q.s. to     1000   ml                                          ______________________________________                                    

One milliliter of this sterile preparation is injected for treatment ofhypertension two times a day.

EXAMPLE 32

A sterile preparation suitable for intramuscular injection andcontaining 60 mg ofN-[(7,8-dimethoxy-2-benzoxepin-1-yl)methyl]-(6,7-dimethoxy-1,2,3,4-tetrahydroquinoline) hydrochloride in each milliliter is prepared from the followingingredients:

    ______________________________________                                        N-[(7,8-dimethoxy-2-benzoxepin-1-yl)methyl]-(6,7-di-                          methoxy-1,2,3,4-tetrahydroisoquinoline) hydrochlo-                            ride                       60     g                                           Benzyl benzoate            200    ml                                          Methylparaben              1.5    g                                           Propylparaben              0.5    g                                           Cottonseed oil q.s. to     1000   ml                                          ______________________________________                                    

One milliliter of this sterile preparation is injected for the treatmentof psychosis at intervals of 8 hours.

EXAMPLE 33

One thousand two-piece hard gelatin capsules for oral use, eachcontaining 30 mg of1-[2-(6,7-dimethoxy-4,4-dimethylisochroman-1-yl)ethyl]-4-(2-methylphenyl)piperazineare prepared from the following ingredients:

    ______________________________________                                        1-[2-(6,7-dimethoxy-4,4-dimethylisochroman-1-yl)ethyl]-                       4-(2-methylphenyl)piperazine                                                                              30      g                                         Lactose, U.S.P.             50      g                                         Starch, U.S.P.              15      g                                         Talc, U.S.P.                3.5     g                                         Calcium stearate            1.5     g                                         ______________________________________                                    

The micronized active ingredient is mixed with the starch-lactosemixture followed by the talc and calcium stearate. The final mixture isthen encapsulated in the usual manner.

One capsule every 12 hours is administered to treat hypertension.

EXAMPLE 34

One thousand two-piece hard gelatin capsules for oral use, eachcontaining 60 mg ofN-[(7,8-dimethoxy-2-benzoxepin-1-yl)methyl]-(6,7-dimethoxy-1,2,3,4-tetrahydroisoquinoline)are prepared from the following ingredients:

    ______________________________________                                        N-[(7,8-dimethoxy-2-benzoxepin-1-yl)methyl]-(6,7-di-                          methoxy-1,2,3,4-tetrahydroisoquinolin)                                                                    60     g                                          Lactose, U.S.P.             50     g                                          Starch, U.S.P.              15     g                                          Talc, U.S.P.                3.5    g                                          Calcium stearate            1.5    g                                          ______________________________________                                    

The micronized active ingredient is mixed with the starch-lactosemixture followed by the talc and calcium stearate. The final mixture isthen encapsulated in the usual manner. One capsule is used every 8 hoursto treat CNS disorders, particularly psychosis.

EXAMPLE 35

An aqueous preparation for oral use containing in each 5 ml (1 teaspoon)50 mg of1-[2-(6,7-dimethoxy-4,4-dimethylisochroman-1-yl)ethyl]-4-(2-methylphenyl)piperazineis prepared from the following ingredients:

    ______________________________________                                        1-[2-(6,7-dimethoxy-4,4-dimethylisochroman-1-yl)-                             ethyl]-4-(2-methylphenyl)piperazine hydrochloride                                                        55     g                                           Methylparaben, U.S.P.      0.75   g                                           Propylparaben, U.S.P.      0.25   g                                           Saccharin sodium           1.25   g                                           Cyclamate sodium           0.25   g                                           Glycerin                   300    ml                                          Tragacanth powder          1.0    g                                           Orange oil flavor          1.0    g                                           F.D. and C. orange dye     0.75   g                                           Deionized water, q.s. to   1000   ml                                          ______________________________________                                    

A dose of one teaspoon per day is useful for treating hypertension.

EXAMPLE 36

An aqueous preparation for oral use containing in each teaspoon (5 ml)75 mg ofN-[(7,8-dimethoxy-2-benzoxepin-1-yl)methyl]-(6,7-dimethoxy-1,2,3,4-tetrahydroisoquinoline)for use in treating psychotic disorders is prepared from the followingingredients:

    ______________________________________                                        N-[(7,8-dimethoxy-2-benzoxepin-1-yl)methyl]-(6,7-di-                          methoxy-1,2,3,4-tetrahydroisoquinoline) hydrochloride                                                    85     g                                           Methylparaben, U.S.P.      0.75   g                                           Propylparaben, U.S.P.      0.25   g                                           Saccharin sodium           1.25   g                                           Cyclamate sodium           0.25   g                                           Glycerin                   300    ml                                          Tragacanth powder          1.0    g                                           Orange oil flavor          1.0    g                                           F.D. and C. orange dye     0.75   g                                           Deionized water, q.s. to   1000   ml                                          ______________________________________                                    

A dose of one to two teaspoons per day is useful in treating CNSdiseases, particularly psychosis.

I claim:
 1. A method of treating psychosis in humans which comprisesadministering systemically to humans an antipsychotic dose of a compoundselected from the group consisting of compounds having the formula##STR810## wherein R¹ is the same or different and is selected from thegroup consisting of alkyl of one through three carbons, inclusive,alkoxy of one through three carbons, inclusive, trihaloalkyl of one ortwo carbons, hydroxy, halo, trihaloalkoxy of one or two carbons ando-methylenedioxy with the proviso that at least one R₁ is hydroxy,alkoxy or o-methylenedioxy;a is one through three; b is zero or one; R₂through R₇ are the same or different and are selected from the groupconsisting of hydrogen, alkyl of one through three carbons, inclusive,hydroxy, alkoxy of one through three carbons; phenyl; halo; cycloalkylof three through six carbons when R₂ and R₃, R₄ and R₅, or R₆ and R₇ aretaken together with the carbon to which they are attached; cycloalkyl offour through seven carbons when R₂ and R₄ or R₄ and R₆ are takentogether with the carbons to which they are attached; and cycloalkyl offive or six carbons, with the overall provisos that no more than onering may be attached to any one carbon and that at least two of R₂through R₇ are hydrogen; R₈ is alkyl of one through three carbons,hydrogen, or phenyl unsubstituted or substituted with a maximum of threesubstituents selected from the group consisting of alkyl of one throughthree carbons, halo, alkoxy of one through three carbons, andtrihaloalkyl of one to two carbons; W is sulfur; and A is selected fromthe group consisting of:(i) --(CH₂)_(n) NR₉ R₁₀, wherein n is one tofive with the proviso that when b is zero, and n is one or two, R₂through R₅ cannot all be hydrogen at the same time; (ii) --(CH₂)m--(OCH₂CH₂)q--NR₂₁ R₂₂, wherein m and q are each one to three, and NR₂₁ R₂₂ isNR₉ R₁₀, ##STR811## wherein NR₉ R₁₀ is a heterocyclic amine selectedfrom the group consisting of ##STR812## and --NHCH₂ CH₂ Ar' wherein R₁₁is alkyl of one through four carbons, 2-furyl, Ar, alkoxy of one tothree carbon atoms, inclusive, Z is selected from the group consistingof pyridyl, pyrimidinyl, triazinyl, pyrazinyl, pyridazinyl, pyrrolyl,imidazolyl, pyrazolyl, furyl, tetrazyl, oxazolyl, quinoxalinyl, andquinazolinyl, wherein each member of the group can be unsubstituted orsubstituted with one or two substituents selected from the groupconsisting of alkyl of one through three carbons, inclusive, alkoxy ofone through three carbons, inclusive, hydroxy, halo, and haloalkyl ofone through three carbons, inclusive; R₁₂ is alkyl or alkoxy of onethrough three carbons, hydroxy, halo, or trihalomethyl, R₁₃ through R₂₀may be the same or different and are selected from the group hydrogenand alkyl of from 1 to 2 carbon atoms, inclusive; c is zero through two;Ar and Ar' are phenyl unsubstituted or substituted with one throughthree substituents selected from the group consisting of alkyl or alkoxyof one through three carbons, hydroxy, halo, and trihaloalkyl ortrihaloalkoxy of one or two carbons and pharmaceutically acceptable acidaddition salts thereof.
 2. A method according to claim 1 wherein thecompound administered is selected from the group consisting of compoundshaving the formula ##STR813## wherein R₁ is the same or different and isselected from the group consisting of alkyl of one through threecarbons, inclusive, alkoxy of one through three carbons, inclusive,trihaloalkyl of one or two carbons, hydroxy, halo, trihaloalkoxy of oneor two carbons and o-methylenedioxy with the proviso that at least oneR₁ is hydroxy, alkoxy or o-methylenedioxy;a is one through three; R₂through R₇ are the same or different and are selected from the groupconsisting of hydrogen, alkyl of one through three carbons, inclusive,hydroxy, alkoxy of one through three carbons; phenyl; halo; cycloalkylof three through six carbons when R₂ and R₃, R₄ and R₅, or R₆ and R₇ aretaken together with the carbon to which they are attached; cycloalkyl offour through seven carbons when R₂ and R₄ or R₄ and R⁶ are takentogether with the carbons to which they are attached; and cycloalkyl offive or six carbons, with the overall provisos that no more than onering may be attached to any one carbon and that at least two of R₂through R₇ are hydrogen; R₈ is alkyl of one through three carbons,hydrogen, or phenyl unsubstituted or substituted with a maximum of threesubstituents selected from the group consisting of alkyl of one throughthree carbons, halo, alkoxy of one through three carbons, andtrihaloalkyl of one to two carbons; W is sulfur; and A is selected fromthe group consisting of:(i) --(CH₂)_(n) NR₉ R₁₀, wherein n is one tofive with the proviso that when b is zero, and n is one or two, R₂through R₅ cannot all be hydrogen at the same time; (ii) --(CH₂)m--(OCH₂CH₂)q--NR₂₁ R₂₂, wherein m and q are each one to three, and NR₂₁ R₂₂ isNR₉ R₁₀, ##STR814## wherein NR₉ R₁₀ is a heterocyclic amine selectedfrom the group consisting of ##STR815## and --NHCH₂ CH₂ Ar' wherein R₁₁is alkyl of one through four carbons, 2-furyl, Ar, alkoxy of one tothree carbon atoms, inclusive, Z is selected from the group consistingof pyridyl, pyrimidinyl, triazinyl, pyrazinyl, pyridazinyl, pyrrolyl,imidazolyl, pyrazolyl, furyl, tetrazyl, oxazolyl, quinoxalinyl, andquinazolinyl, wherein each member of the group can be unsubstituted orsubstituted with one or two substituents selected from the groupconsisting of alkyl of one through three carbons, inclusive, alkoxy ofone through three carbons, inclusive, hydroxy, halo, and haloalkyl ofone through three carbons, inclusive; R₁₂ is alkyl or alkoxy of onethrough three carbons, hydroxy, halo, or trihalomethyl, R₁₃ through R₂₀may be the same or different and are selected from the group hydrogenand alkyl of from 1 to 2 carbon atoms, inclusive; c is zero through two;Ar and Ar' are phenyl unsubstituted or substituted with one throughthree substituents selected from the group consisting of alkyl or alkoxyof one through three carbons, hydroxy, halo, and trihaloalkyl ortrihaloalkoxy of one or two carbons and pharmaceutically acceptable acidaddition salts thereof.
 3. A method according to claim 1 where thecompound administered is selected from the group consisting of compoundshaving the formula ##STR816## wherein R₁ is the same or different and isselected from the group consisting of alkyl of one through threecarbons, inclusive, alkoxy of one through three carbons, inclusive,trihaloalkyl of one or two carbons, hydroxy, halo, trihaloalkoxy of oneor two carbons and o-methylenedioxy with the proviso that at least oneR₁ is hydroxy, alkoxy or o-methylenedioxy;a is one through three; R₂through R₅ are the same or different and are selected from the groupconsisting of hydrogen, alkyl of one through three carbons, inclusive,hydroxy, alkoxy of one through three carbons; phenyl; halo; cycloalkylof three through six carbons when R₂ and R₃ or R₄ and R₅ are takentogether with the carbon to which they are attached; cycloalkyl of fourthrough seven carbons when R₂ and R₄ are taken together with the carbonsto which they are attached; and cycloalkyl of five or six carbons, withthe overall provisos that no more than one ring may be attached to anyone carbon and that at least two of R₂ through R₅ are hydrogen; R₈ isalkyl of one through three carbons, hydrogen, or phenyl unsubstituted orsubstituted with a maximum of three substituents selected from the groupconsisting of alkyl of one through three carbons, halo, alkoxy of onethrough three carbons, and trihaloalkyl of one to two carbons; W issulfur; and A is selected from the group consisting of:(i) --(CH₂)_(n)NR₉ R₁₀, wherein n is one to five with the proviso that when b is zero,and n is one or two, R₂ through R₅ cannot all be hydrogen at the sametime; (ii) --(CH₂)m--(OCH₂ CH₂)q-NR₂₁ R₂₂, wherein m and q are each oneto three, and NR₂₁ R₂₂ is NR₉ R₁₀, ##STR817## wherein NR₉ R₁₀ is aheterocyclic amine selected from the group consisting of ##STR818## and--NHCH₂ CH₂ Ar' wherein R₁₁ is alkyl of one through four carbons,2-furyl, Ar, alkoxy of one to three carbon atoms, inclusive, Z isselected from the group consisting of pyridyl, pyrimidinyl, triazinyl,pyrazinyl, pyridazinyl, pyrrolyl, imidazolyl, pyrazolyl, furyl,tetrazyl, oxazolyl, quinoxalinyl, and quinazolinyl, wherein each memberof the group can be unsubstituted or substituted with one or twosubstituents selected from the group consisting of alkyl of one throughthree carbons, inclusive, alkoxy of one through three carbons,inclusive, hydroxy, halo, and haloalkyl of one through three carbons,inclusive; R₁₂ is alkyl or alkoxy of one through three carbons, hydroxy,halo, or trihalomethyl, R₁₃ through R₂₀ may be the same or different andare selected from the group hydrogen and alkyl of from 1 to 2 carbonatoms, inclusive; c is zero through two; Ar and Ar' are phenylunsubstituted or substituted with one through three substituentsselected from the group consisting of alkyl or alkoxy of one throughthree carbons, hydroxy, halo, and trihaloalkyl or trihaloalkoxy of oneor two carbons and pharmaceutically acceptable acid addition saltsthereof.
 4. A method according to claim 2 when A is the group--(CH₂)_(n) NR₉ R₁₀.
 5. A method according to claim 3 when A is thegroup --(CH₂)_(n) NR₉ R₁₀.
 6. A method according to claim 5 wherein a istwo or three, R₂ through R₅ are the same or different and are selectedfrom the group consisting of hydrogen, alkyl of one through three carbonatoms, inclusive, and cycloalkyl of four through seven carbon atoms,inclusive, when R₂ and R₄ are taken together with the carbon atom towhich they are attached, with the proviso that when R₃ through R₅ arehydrogen, R₂ cannot be hydrogen.
 7. A method according to claim 6wherein NR₉ R₁₀ is selected from the group consisting of ##STR819## ARand Ar' are phenyl unsubstituted or substituted with one through threesubstituents selected from the group consisting of alkyl or alkoxy ofone through three carbons, hydroxy, halo, and trihaloalkyl ortrihaloalkoxy of one or two carbons; andR₁₂ is selected from the groupconsisting of halo, hydroxy, alkyl of from one to three carbon atoms,inclusive, alkoxy of from one to three carbon atoms, inclusive andtrihaloalkyl of from one to two carbon atoms, inclusive, and c is 1 or2.
 8. A method according to claim 7 wherein (R₁)_(a) is di-lower alkoxyof from one to four carbon atoms, inclusive; R₂ and R₃ are both loweralkyl of from one to four carbon atoms, inclusive; and R₄ and R₅ areboth hydrogen.
 9. A method according to claim 3 wherein a is two orthree.